440 results on '"TUMOR suppressor proteins"'
Search Results
2. FLT(3)-ing about: the search for the best inhibitor.
- Author
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Stone RM
- Subjects
- Humans, Sorafenib, fms-Like Tyrosine Kinase 3 genetics, Tumor Suppressor Proteins, Leukemia, Myeloid, Acute
- Published
- 2023
- Full Text
- View/download PDF
3. 19-nor vitamin-D analogs: a new class of potent inhibitors of proliferation and inducers of differentiation of human myeloid leukemia cell lines.
- Author
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Asou, H, Koike, M, Elstner, E, Cambell, M, Le, J, Uskokovic, M R, Kamada, N, and Koeffler, H P
- Subjects
Cell Cycle: drug effects ,Cell Cycle Proteins ,Cell Differentiation: drug effects ,Cell Division: drug effects ,Cyclin-Dependent Kinase Inhibitor p27 ,Drug Resistance ,Neoplasm ,G1 Phase ,Gene Expression Regulation ,Leukemic: drug effects ,HL-60 Cells: drug effects ,Humans ,Leukemia ,Myeloid: pathology ,Microtubule-Associated Proteins: biosynthesis ,genetics ,Molecular Structure ,Neoplasm Proteins: biosynthesis ,genetics ,Nitroblue Tetrazolium ,Oxidation-Reduction ,Structure-Activity Relationship ,Tretinoin: pharmacology ,Tumor Cells ,Cultured: drug effects ,Tumor Suppressor Proteins ,Vitamin D: analogs & derivatives ,chemistry ,pharmacology - Abstract
We have studied the in vitro biological activities and mechanisms of action of 1,25-dihydroxyvitamin D3 (1,25D3) and nine potent 1,25D3 analogs on proliferation and differentiation of myeloid leukemia cell lines (HL-60, retinoic acid-resistant HL-60 [RA-res HL-60], NB4 and Kasumi-1). The common novel structural motiff for almost all the analogs included removal of C-19 (19-nor); each also had unsaturation of the side chain. All the compounds were potent; for example, the concentration of analogs producing a 50% clonal inhibition (ED50) ranged between 1 x 10(-9) to 4 x 10(-11) mol/L when using the HL-60 cell line. The most active compound [1, 25(OH)2-16,23E-diene-26-trifluoro-19-nor-cholecalciferol (Ro 25-9716)] had an ED50 of 4 x 10(-11) mol/L; in contrast, the 1,25D3 produced an ED50 of 10(-9) mol/L with the HL-60 target cells. Ro 25-9716 (10(-9) mol/L, 3 days) was a strong inducer of myeloid differentiation because it caused 92% of the HL-60 cells to express CD11b and 75% of these cells to reduce nitroblue tetrazolium (NBT). This compound (10(-8) mol/L, 4 days) also caused HL-60 cells to arrest in the G1 phase of the cell cycle (88% cells in G1 v 48% of the untreated control cells). The p27(kip-1), a cyclin-dependent kinase inhibitor which is important in blocking the cell cycle, was induced more quickly and potently by Ro 25-9716 (10(-7) mol/L, 0 to 5 days) than by 1,25D3, suggesting a possible mechanism by which these analogs inhibit proliferation of leukemic growth. The NB4 promyelocytic leukemia cells cultured with the Ro 25-9716 were also inhibited in their clonal proliferation (ED50, 5 x 10(-11) mol/L) and their expression of CD11b was enhanced (80% positive [10(-9) mol/L, 4 days] v 27% untreated NB4 cells). Moreover, the combination of Ro 25-9716 (10(-9) mol/L) and all-trans retinoic acid (ATRA, 10(-7) mol/L) induced 92% of the NB4 cells to reduce NBT, whereas only 26% of the cells became NBT positive after a similar exposure to the combination of 1,25D3 and ATRA. Surprisingly, Ro 25-9716 also inhibited the clonal growth of poorly differentiated leukemia cell lines (RA-res HL-60 [ED50, 4 x 10(-9) mol/L] and Kasumi-1 [ED50, 5 x 10(-10) mol/L]). For HL-60 cells, Ro 25-9716 markedly decreased the percent of the cells in S phase of the cell cycle and increased the expression of the cyclin-dependent kinase inhibitor, p27(kip-1). In summary, 19-nor vitamin D3 compounds strongly induced differentiation and inhibited clonal proliferation of various myeloid leukemia cell lines, suggesting a therapeutic niche for their use in myeloid leukemia.
- Published
- 1998
4. Single-cell RNA-seq reveals developmental plasticity with coexisting oncogenic states and immune evasion programs in ETP-ALL
- Author
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Jon C. Aster, Noori Sotudeh, Jens G. Lohr, David T. Teachey, Guangwu Guo, Monica S. Nair, Tushara Vijaykumar, Praveen Anand, Huiyoung Yun, Anna Jollyette Rogers, Daniel J. DeAngelo, Yotam Drier, Andrew E. Place, Sayalee Potdar, Julia Frede, Tiffaney Vincent, Andrew A. Lane, Madhu M. Ouseph, Amy Guillaumet-Adkins, Jake A. Kloeber, Randi Isenhart, Lewis B. Silverman, Bradley E. Bernstein, Leili Niu, Marian H. Harris, Birgit Knoechel, and Valeriya Dimitrova
- Subjects
0301 basic medicine ,Lymphoid Neoplasia ,Cell cycle checkpoint ,Tumor Suppressor Proteins ,Immunology ,Cell Biology ,Hematology ,Cell cycle ,Biology ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Biochemistry ,03 medical and health sciences ,Leukemia ,030104 developmental biology ,0302 clinical medicine ,Immune system ,030220 oncology & carcinogenesis ,Acute lymphocytic leukemia ,Cancer cell ,medicine ,Cancer research ,Humans ,Stem cell ,Transcription factor - Abstract
Lineage plasticity and stemness have been invoked as causes of therapy resistance in cancer, because these flexible states allow cancer cells to dedifferentiate and alter their dependencies. We investigated such resistance mechanisms in relapsed/refractory early T-cell progenitor acute lymphoblastic leukemia (ETP-ALL) carrying activating NOTCH1 mutations via full-length single-cell RNA sequencing (scRNA-seq) of malignant and microenvironmental cells. We identified 2 highly distinct stem-like states that critically differed with regard to cell cycle and oncogenic signaling. Fast-cycling stem-like leukemia cells demonstrated Notch activation and were effectively eliminated in patients by Notch inhibition, whereas slow-cycling stem-like cells were Notch independent and rather relied on PI3K signaling, likely explaining the poor efficacy of Notch inhibition in this disease. Remarkably, we found that both stem-like states could differentiate into a more mature leukemia state with prominent immunomodulatory functions, including high expression of the LGALS9 checkpoint molecule. These cells promoted an immunosuppressive leukemia ecosystem with clonal accumulation of dysfunctional CD8+ T cells that expressed HAVCR2, the cognate receptor for LGALS9. Our study identified complex interactions between signaling programs, cellular plasticity, and immune programs that characterize ETP-ALL, illustrating the multidimensionality of tumor heterogeneity. In this scenario, combination therapies targeting diverse oncogenic states and the immune ecosystem seem most promising to successfully eliminate tumor cells that escape treatment through coexisting transcriptional programs.
- Published
- 2021
5. GADD45g acts as a novel tumor suppressor, and its activation suggests new combination regimens for the treatment of AML
- Author
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Dan Guo, Wenqi Zhu, Qian Ren, Tao Cheng, Peiwen Zhang, Nan Wang, Jing Yin, Yangyang Zhao, Na You, and Xiao-Tong Ma
- Subjects
THP-1 Cells ,medicine.drug_class ,DNA damage ,Immunology ,HL-60 Cells ,Mice, SCID ,Biochemistry ,Tyrosine-kinase inhibitor ,Romidepsin ,Mice ,Mice, Inbred NOD ,Depsipeptides ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Animals ,Humans ,Medicine ,Benzothiazoles ,neoplasms ,biology ,business.industry ,Phenylurea Compounds ,Tumor Suppressor Proteins ,Intracellular Signaling Peptides and Proteins ,Myeloid leukemia ,Azepines ,U937 Cells ,Cell Biology ,Hematology ,Triazoles ,medicine.disease ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Leukemia, Myeloid, Acute ,Leukemia ,Histone ,fms-Like Tyrosine Kinase 3 ,Mutation ,GADD45G ,Cancer research ,biology.protein ,business ,Tyrosine kinase ,medicine.drug - Abstract
Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy for which there is an unmet need for novel treatment strategies. Here, we characterize the growth arrest and DNA damage-inducible gene gamma (GADD45g) as a novel tumor suppressor in AML. We show that GADD45g is preferentially silenced in AML, especially in AML with FMS-like tyrosine kinase 3–internal tandem duplication (FLT3-ITD) mutations and mixed-lineage leukemia (MLL)-rearrangements, and reduced expression of GADD45g is correlated with poor prognosis in patients with AML. Upregulation of GADD45g impairs homologous recombination DNA repair, leading to DNA damage accumulation, and dramatically induces apoptosis, differentiation, and growth arrest and increases sensitivity of AML cells to chemotherapeutic drugs, without affecting normal cells. In addition, GADD45g is epigenetically silenced by histone deacetylation in AML, and its expression is further downregulated by oncogenes FLT3-ITD and MLL-AF9 in patients carrying these genetic abnormalities. Combination of the histone deacetylase 1/2 inhibitor romidepsin with the FLT3 tyrosine kinase inhibitor AC220 or the bromodomain inhibitor JQ1 exerts synergistic antileukemic effects on FLT3-ITD+ and MLL-AF9+ AML, respectively, by dually activating GADD45g. These findings uncover hitherto unreported evidence for the selective antileukemic role of GADD45g and provide novel strategies for the treatment of FLT3-ITD+ and MLL-AF9+ AML.
- Published
- 2021
6. BCL11B, the Cerberus of human leukemia
- Author
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Jules P.P. Meijerink
- Subjects
Human leukemia ,Leukemia ,Lymphoid Neoplasia ,Tumor Suppressor Proteins ,BCL11B ,Immunology ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,Repressor Proteins ,Cerberus (protein) ,hemic and lymphatic diseases ,medicine ,Cancer research ,Humans ,Transcription Factors - Abstract
Acute leukemias (ALs) of ambiguous lineage are a heterogeneous group of high-risk leukemias characterized by coexpression of myeloid and lymphoid markers. In this study, we identified a distinct subgroup of immature acute leukemias characterized by a broadly variable phenotype, covering acute myeloid leukemia (AML, M0 or M1), T/myeloid mixed-phenotype acute leukemia (T/M MPAL), and early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). Rearrangements at 14q32/BCL11B are the cytogenetic hallmark of this entity. In our screening of 915 hematological malignancies, there were 202 AML and 333 T-cell acute lymphoblastic leukemias (T-ALL: 58, ETP; 178, non-ETP; 8, T/M MPAL; 89, not otherwise specified). We identified 20 cases of immature leukemias (4% of AML and 3.6% of T-ALL), harboring 4 types of 14q32/BCL11B translocations: t(2,14)(q22.3;q32) (n = 7), t(6;14)(q25.3;q32) (n = 9), t(7;14)(q21.2;q32) (n = 2), and t(8;14)(q24.2;q32) (n = 2). The t(2;14) produced a ZEB2-BCL11B fusion transcript, whereas the other 3 rearrangements displaced transcriptionally active enhancer sequences close to BCL11B without producing fusion genes. All translocations resulted in the activation of BCL11B, a regulator of T-cell differentiation associated with transcriptional corepressor complexes in mammalian cells. The expression of BCL11B behaved as a disease biomarker that was present at diagnosis, but not in remission. Deregulation of BCL11B co-occurred with variants at FLT3 and at epigenetic modulators, most frequently the DNMT3A, TET2, and/or WT1 genes. Transcriptome analysis identified a specific expression signature, with significant downregulation of BCL11B targets, and clearly separating BCL11B AL from AML, T-ALL, and ETP-ALL. Remarkably, an ex vivo drug-sensitivity profile identified a panel of compounds with effective antileukemic activity.
- Published
- 2021
7. Deletion of Pten in CD45-expressing cells leads to development of T-cell lymphoblastic lymphoma but not myeloid malignancies.
- Author
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Mirantes, Cristina, Dosil, Maria Alba, Hills, David, Jian Yang, Eritja, Núria, Santacana, Maria, Gatius, Sònia, Vilardell, Felip, Medvinsky, Alexander, Matias-Guiu, Xavier, and Dolcet, Xavier
- Subjects
- *
T cells , *LYMPHOMAS , *TUMOR suppressor genes , *TUMOR suppressor proteins , *PHOSPHATIDYLINOSITOLS , *CELL proliferation - Abstract
Since its discovery in the late 1990s, Pten has turned out to be one of the most important tumor suppressor genes. Pten loss results in increased activation of the phosphatidylinositol 3-kinase/Akt signaling pathway, which is associated with increased proliferation, survival, and neoplastic growth. Here, we have addressed the effects of conditional deletion of Pten in hematopoietic cells by crossing Pten conditional knockout mice with a knock-in mouse expressing the Cre recombinase in the CD45 locus. CD45 is also known as leukocyte common antigen, and it is expressed in virtually all white cells and in hematopoietic stem cells. Using a reporter mouse, we demonstrate that CD45:Cre mouse displays recombinase activity in both myeloid and lymphoid cells. However, deletion of Pten in CD45-expressing cells induces development of T-cell acute lymphoblastic leukemia and lymphoma, but not other hematologic malignancies. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
8. Dicerl imparts essential survival cues in Notch-driven T-ALL via miR-21-mediated tumor suppressor Pdcd4 repression.
- Author
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Junker, Fabian, Chabloz, Antoine, Koch, Ute, and Radtke, Freddy
- Subjects
- *
MICRORNA , *LYMPHOBLASTIC leukemia , *T cells , *TUMOR suppressor genes , *TUMOR suppressor proteins , *CANCER - Abstract
The modulatory function of individual microRNAs (miRNAs) in Notch-driven T-cell acute lymphoblastic leukemias (T-ALLs) has recently been established. Although protumorigenic and tumor-suppressive miRNAs are implicated in disease onset in murine models of Notch-driven T-cell leukemia, whether Dicer1-processed miRNAs are essential for Notch-driven T-ALL is currently unknown. Here we used conditional and inducible genetic loss-of-function approaches to test whether the development and maintenance of Notch-driven T-ALL was dependent on Dicer1 function. Mice with specific inactivation of both Dicer1 alleles in the T-cell lineage did not develop Notch-driven T-ALL. In contrast, loss of 1 functional Dicer1 allele did not significantly perturb T-ALL onset and tumor progression. Inducible inactivation of Dicer1 in early stage polyclonal T-ALL cells was sufficient to abrogate T-ALL progression in leukemic mice, whereas late-stage monoclonal T-ALL cells were counterselected against loss of Dicer1. Lineage-tracing experiments revealed that Dicer1 deficiency led to the induction of apoptosis in T-ALL cells, whereas cell cycle progression remained unaltered. Through microarray-based miRNA profiling, we identified miR-21 as a previously unrecognized miRNA deregulated in both mouse and human T-ALL. Herein, we demonstrate that miR-21 regulates T-ALL cell survival via repression of the tumor suppressor Pdcd4. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
9. Lyn sustains oncogenic signaling in chronic lymphocytic leukemia by strengthening SET-mediated inhibition of PP2A.
- Author
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Zonta, Francesca, Pagano, Mario Angelo, Trentin, Livio, Tibaldi, Elena, Frezzato, Federica, Trimarco, Valentina, Facco, Monica, Zagotto, Giuseppe, Pavan, Valeria, Ribaudo, Giovanni, Bordin, Luciana, Semenzato, Gianpietro, and Brunati, Anna Maria
- Subjects
- *
CHRONIC lymphocytic leukemia , *PROTEIN-tyrosine phosphatase , *PHOSPHOTYROSINE , *THREONINE , *TUMOR suppressor proteins , *PHOSPHORYLATION , *APOPTOSIS - Abstract
Aberrant protein kinase activities, and the consequent dramatic increase of Ser/Thr and -Tyr phosphorylation, promote the deregulation of the survival pathways in chronic lymphocytic leukemia (CLL), which is crucial to the pathogenesis and progression of the disease. In this study, we show that the tumor suppressor protein phosphatase 2A (PP2A), one of the major Ser/Thr phosphatase, is in an inhibited form because of the synergistic contribution of 2 events, the interaction with its physiological inhibitor SET and the phosphorylation of Y307 of the catalytic subunit of PP2A. The latter event is mediated by Lyn, a Src family kinase previously found to be overexpressed, delocalized and constitutively active in CLL cells. This Lyn/PP2A axis accounts for the persistent high level of phosphorylation of the phosphatase's targets and represents a key connection linking phosphotyrosine- and phosphoserine/threonine-mediated oncogenic signals. The data herein presented show that the disruption of the SET/PP2A complex by a novel FTY720-analogue (MP07-66) devoid of immunosuppressive effects leads to the reactivation of PP2A, which in turn triggers apoptosis of CLL cells. When used in combination with SFK inhibitors, the action of MP07-66 is synergistically amplified, providing a new option in the therapeutic strategy for CLL patients. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
10. Rationale for targeting the pre-B-cell receptor signaling pathway in acute lymphoblastic leukemia.
- Author
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Müschen, Markus
- Subjects
- *
LYMPHOBLASTIC leukemia , *B cell receptors , *TUMOR suppressor proteins , *B cells , *LYMPHOCYTIC leukemia - Abstract
Inhibitors of B-cell receptor (BCR) and pre-BCR signaling were successfully introduced into patient care for various subtypes of mature B-cell lymphoma, (e.g, ibrutinib, idelalisib). Acute lymphoblastic leukemia (ALL) typically originates from pre-B cells that critically depend on survival signals emanating from a functional pre-BCR. However, whether patients with ALL benefit from treatment with (pre-) BCR inhibitors has not been explored. Recent data suggest that the pre-BCR functions as tumor suppressor in the majority of cases of human ALL. However, a distinct subset of human ALL is selectively sensitive to pre-BCR antagonists. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
11. Decitabine priming enhances the antileukemic effects of exportin 1 (XPOl) selective inhibitor selinexor in acute myeloid leukemia.
- Author
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Ranganathan, Parvathi, Xueyan Yu, Santhanam, Ramasamy, Hofstetter, Jessica, Walker, Alison, Walsh, Katherine, Bhatnagar, Bhavana, Klisovic, Rebecca, Vasu, Sumithira, Phelps, Mitch A., Devine, Steven, Shacham, Sharon, Kauffman, Michael, Marcucci, Guido, Blum, William, and Garzon, Ramiro
- Subjects
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DECITABINE , *ACUTE myeloid leukemia , *RECEPTOR antibodies , *HORMONE receptors , *TUMOR suppressor proteins , *ENZYME inhibitors , *PROGNOSIS , *THERAPEUTICS - Abstract
The prognosis of acute myeloid leukemia (AML) is poor, highlighting the need for novel treatments. Hypomethylating agents, including decitabine are used to treat elderly AML patients with relative success. Targeting nuclear export receptor (exportin 1 [XPO1]) is a novel approach to restore tumor suppressor (TS) function in AML. Here, we show that sequential treatment of AML blasts with decitabine followed by selinexor (XPO1 inhibitor) enhances the antileukemic effects of selinexor. These effects could be mediated by the re-expression of a subset of TSs (CDKN1A and FOXO3A) that are epigenetically silenced via DNA methylation, and cytoplasmic-nuclear trafficking is regulated by XPO1. We observed a significant upregulation of CDKN1A and FOXO3A in decitabine- versus control-treated cells. Sequential treatment of decitabine followed by selinexor in an MV4-11 xenograft model significantly improved survival compared with selinexor alone. On the basis of these preclinical results, a phase 1 clinical trial of decitabine followed by selinexor in elderly patients with AML has been initiated. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
12. 'Double-hit' of DUSP22 and TP63 rearrangements in anaplastic large cell lymphoma, ALK-negative
- Author
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Andrew L. Feldman and Kennosuke Karube
- Subjects
Double hit ,Immunology ,Tp63 gene ,Biology ,Biochemistry ,TP63 ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Anaplastic lymphoma kinase ,Humans ,Anaplastic Lymphoma Kinase ,Anaplastic large-cell lymphoma ,Cyclophosphamide ,Aged ,Gene Rearrangement ,Large cell ,Tumor Suppressor Proteins ,Cell Biology ,Hematology ,Gene rearrangement ,medicine.disease ,Lymphoma ,Doxorubicin ,Vincristine ,Cancer research ,Dual-Specificity Phosphatases ,Lymphoma, Large-Cell, Anaplastic ,Mitogen-Activated Protein Kinase Phosphatases ,Prednisone ,Female ,Transcription Factors - Published
- 2020
13. Polycomb repressive complex 2 (PRC2) suppresses Eμ-myc lymphoma.
- Author
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Lee, Stanley C. W., Phipson, Belinda, Hyland, Craig D., Huei San Leong, Allan, Rhys S., Lun, Aaron, Hilton, Douglas J., Nutt, Stephen L., Blewitt, Marnie E., Smyth, Gordon K., Alexander, Warren S., and Majewski, Ian J.
- Subjects
- *
POLYCOMB group proteins , *CANCER risk factors , *B cell lymphoma , *T cells , *TUMOR suppressor proteins , *HETEROZYGOSITY , *TUMORS - Abstract
Deregulation of polycomb group complexes polycomb repressive complex 1 (PRC1) and 2 (PRC2) is associated with human cancers. Although inactivating mutations in PRC2-encoding genes EZH2, EED, and SUZ12 are present in T-cell acute lymphoblastic leukemia and in myeloid malignancies, gain-of-function mutations in EZH2 are frequently observed in B-cell lymphoma, implying disease-dependent effects of individual mutations. We show that, in contrast to PRC1, PRC2 is a tumor suppressor in Eμ-myc lymphomagenesis, because disease onset was accelerated by heterozygosity for Suz12 or by short hairpin RNA-mediated knockdown of Suz12 or Ezh2. Accelerated lymphomagenesis was associated with increased accumulation of B-lymphoid cells in the absence of effects on apoptosis or cell cycling. However, Suz12-deficient B-lymphoid progenitors exhibit enhanced serial clonogenicity. Thus, PRC2 normally restricts the self-renewal of B-lymphoid progenitors, the disruption of which contributes to lymphomagenesis. This finding provides new insight regarding the functional contribution of mutations in PRC2 in a range of leukemias. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
14. Antiphospholipid antibodies induce thrombosis by PP2A activation via apoER2-Dab2-SHC1 complex formation in endothelium
- Author
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Anastasia Sacharidou, Jane E. Salmon, Philip W. Shaul, Lance S. Terada, David Y. Hui, Ken L. Chambliss, Chieko Mineo, Yu-min P Shen, Victoria Ulrich, and Joachim Herz
- Subjects
Male ,0301 basic medicine ,Src Homology 2 Domain-Containing, Transforming Protein 1 ,Low-density lipoprotein receptor-related protein 8 ,Nitric Oxide Synthase Type III ,Endothelium ,Protein subunit ,Immunology ,030204 cardiovascular system & hematology ,Models, Biological ,Biochemistry ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Enos ,Heterotrimeric G protein ,medicine ,Animals ,Humans ,Protein Phosphatase 2 ,Protein kinase B ,LDL-Receptor Related Proteins ,Adaptor Proteins, Signal Transducing ,Autoantibodies ,biology ,Chemistry ,Tumor Suppressor Proteins ,Endothelial Cells ,Thrombosis ,Cell Biology ,Hematology ,Protein phosphatase 2 ,biology.organism_classification ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Multiprotein Complexes ,Antibodies, Antiphospholipid ,Endothelium, Vascular ,Apoptosis Regulatory Proteins ,Proto-oncogene tyrosine-protein kinase Src - Abstract
In the antiphospholipid syndrome (APS), antiphospholipid antibody (aPL) recognition of β2 glycoprotein I promotes thrombosis, and preclinical studies indicate that this is due to endothelial nitric oxide synthase (eNOS) antagonism via apolipoprotein E receptor 2 (apoER2)-dependent processes. How apoER2 molecularly links these events is unknown. Here, we show that, in endothelial cells, the apoER2 cytoplasmic tail serves as a scaffold for aPL-induced assembly and activation of the heterotrimeric protein phosphatase 2A (PP2A). Disabled-2 (Dab2) recruitment to the apoER2 NPXY motif promotes the activating L309 methylation of the PP2A catalytic subunit by leucine methyl transferase-1. Concurrently, Src homology domain-containing transforming protein 1 (SHC1) recruits the PP2A scaffolding subunit to the proline-rich apoER2 C terminus along with 2 distinct regulatory PP2A subunits that mediate inhibitory dephosphorylation of Akt and eNOS. In mice, the coupling of these processes in endothelium is demonstrated to underlie aPL-invoked thrombosis. By elucidating these intricacies in the pathogenesis of APS-related thrombosis, numerous potential new therapeutic targets have been identified.
- Published
- 2018
15. Prognostic impact of t(16;21)(p11;q22) and t(16;21)(q24;q22) in pediatric AML: a retrospective study by the I-BFM Study Group
- Author
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Marry M. van den Heuvel-Eibrink, Henrik Hasle, Jenny L. Smith, Jan Stary, Soheil Meshinchi, Małgorzata Czogała, Dirk Reinhardt, C. Michel Zwaan, Jonas Abrahamsson, Betsy A. Hirsch, Martin Zimmermann, Wendy Cuccuini, Tanja A. Gruber, Sanne Noort, Daisuke Tomizawa, Michael Dworzak, Daniel K. Cheuk, Martina Pigazzi, Franco Locatelli, Barbara De Moerloose, Edwin Sonneveld, Todd A. Alonzo, Susana C. Raimondi, Nira Arad-Cohen, Rhonda E. Ries, and Pediatrics
- Subjects
Male ,Myeloid ,Chromosomes, Human, Pair 21 ,Biochemistry ,Immunology ,Hematology ,Cell Biology ,Medizin ,Gastroenterology ,Translocation, Genetic ,0302 clinical medicine ,AML ,hemic and lymphatic diseases ,Cumulative incidence ,Child ,Myeloid Neoplasia ,Gene Expression Regulation, Leukemic ,Hazard ratio ,Myeloid leukemia ,Prognosis ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,030220 oncology & carcinogenesis ,Child, Preschool ,Cohort ,Core Binding Factor Alpha 2 Subunit ,Female ,medicine.medical_specialty ,Adolescent ,myeloid neoplasia ,acute myeloid leukemia ,children ,03 medical and health sciences ,Transcriptional Regulator ERG ,White blood cell ,Internal medicine ,medicine ,Humans ,Retrospective Studies ,business.industry ,Tumor Suppressor Proteins ,Infant ,Retrospective cohort study ,medicine.disease ,Repressor Proteins ,RNA-Binding Protein FUS ,business ,Transcriptome ,Chromosomes, Human, Pair 16 ,030215 immunology - Abstract
To study the prognostic relevance of rare genetic aberrations in acute myeloid leukemia (AML), such as t(16;21), international collaboration is required. Two different types of t(16;21) translocations can be distinguished: t(16;21)(p11;q22), resulting in the FUS-ERG fusion gene; and t(16;21)(q24;q22), resulting in RUNX1-core binding factor (CBFA2T3). We collected data on clinical and biological characteristics of 54 pediatric AML cases with t(16;21) rearrangements from 14 international collaborative study groups participating in the international Berlin-Frankfurt-Münster (I-BFM) AML study group. The AML-BFM cohort diagnosed between 1997 and 2013 was used as a reference cohort. RUNX1-CBFA2T3 (n = 23) had significantly lower median white blood cell count (12.5 × 109/L, P = .03) compared with the reference cohort. FUS-ERG rearranged AML (n = 31) had no predominant French-American-British (FAB) type, whereas 76% of RUNX1-CBFA2T3 had an M1/M2 FAB type (M1, M2), significantly different from the reference cohort (P = .004). Four-year event-free survival (EFS) of patients with FUS-ERG was 7% (standard error [SE] = 5%), significantly lower compared with the reference cohort (51%, SE = 1%, P < .001). Four-year EFS of RUNX1-CBFA2T3 was 77% (SE = 8%, P = .06), significantly higher compared with the reference cohort. Cumulative incidence of relapse was 74% (SE = 8%) in FUS-ERG, 0% (SE = 0%) in RUNX1-CBFA2T3, compared with 32% (SE = 1%) in the reference cohort (P < .001). Multivariate analysis identified both FUS-ERG and RUNX1-CBFA2T3 as independent risk factors with hazard ratios of 1.9 (P < .0001) and 0.3 (P = .025), respectively. These results describe 2 clinically relevant distinct subtypes of pediatric AML. Similarly to other core-binding factor AMLs, patients with RUNX1-CBFA2T3 rearranged AML may benefit from stratification in the standard risk treatment, whereas patients with FUS-ERG rearranged AML should be considered high-risk.
- Published
- 2018
16. COP1 targets C/EBPα for degradation and induces acute myeloid leukemia via Tribl.
- Author
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Akihiro Yoshida, Jun-ya Kato, Ikuko Nakamae, and Noriko Yoneda-Kato
- Subjects
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ACUTE myeloid leukemia , *NEOPLASTIC cell transformation , *TUMOR suppressor proteins , *UBIQUITIN ligases , *BONE marrow transplantation , *LEUKEMIA etiology - Abstract
The ubiquitin ligase constitutively photomorphogenic 1 (COP1) is involved in many biological responses in mammalian cells, but its role in tumorigenesis remains unclear. Here we show that COP1 is a ubiquitin ligase for the tumor suppressor CCAAT/enhancer-binding protein (C/EBPα) and promotes its degradation in vivo, thereby blocking myeloid differentiation of hematopoietic cells for tumorigenesis. In this process, mammalian homolog of Tribbles, Tribl, which contains a COP1-binding motif, is essential for down-regulation of C/EBPα expression. Murine bone marrow transplantation experiments showed that coex-pression of COP1 accelerates development of acute myeloid leukemia induced by Tribl, which pathologically resembles that of p42C/EBPα-deficient mice. Interestingly, coexpression of ligase activity-deficient COP1 mutant abrogated Tribl-induced leukemogenesis. These results indicate that COP1 and Tribl act as an oncoprotein complex functioning upstream of C/EBPα, and its ligase activity is crucial for leukemogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
17. Prognostic impact and targeting of CRM1 in acute myeloid leukemia.
- Author
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Kojima, Kensuke, Kornblau, Steven M., Ruvolo, Vivian, Dilip, Archana, Duvvuri, Seshagiri, Davis, R. Eric, Min Zhang, Zhiqiang Wang, Coombes, Kevin R., Nianxiang Zhang, Yi Hua Qiu, Burks, Jared K., Kantarjian, Hagop, Shacham, Sharon, Kauffman, Michael, and Andreeff, Michael
- Subjects
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PROTEIN receptors , *TUMOR suppressor genes , *ACUTE myeloid leukemia , *TUMOR suppressor proteins , *MULTIVARIATE analysis , *APOPTOSIS inhibition - Abstract
Chromosomal region maintenance 1 (CRM1) is a nuclear export receptor recognizing proteins bearing a leucine-rich nuclear export signal. CRM1 is involved in nuclear export of tumor suppressors such as p53. We investigated the prognostic significance of CRM1 in acute myeloid leukemia (AML) and effects of a novel small-molecule selective inhibitor of CRM1. CRM1 protein expression was determined in 511 newly diagnosed AML patients and was correlated with mouse double minute 2 (MDM2) and p53 levels. High CRM1 expression was associated with short survival of patients and remained an adverse prognostic factor in multivariate analysis. CRM1 inhibitor KPT-185 induced mainly full-length p53 and apoptosis in a p53-dependent manner, whereas inhibition of proliferation was p53 independent. Patient samples with p53 mutations showed low sensitivity to KPT-185. Nuclear retention of p53 induced by CRM1 inhibition synergized with increased levels of p53 induced by MDM2 inhibition in apoptosis induction. KPT-185 and Nutlin-3a, alone and in combination, induced synergistic apoptosis in patient-derived CD34+/CD38- AML, but not in normal progenitor cells. Data suggest that CRM1 exerts an antiapoptotic function and is highly prognostic in AML. We propose a novel combinatorial approach for the therapy of AML, aimed at maximal activation of p53-mediated apoptosis by concomitant MDM2 and CRM1 inhibition. [ABSTRACT FROM AUTHOR]
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- 2013
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18. Targeting transcription factor SALL4 in acute myeloid leukemia by interrupting its interaction with an epigenetic complex.
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Dimitrov, Todor, Kol Jia Yong, Tatetsu, Hiro, Ha-won Jeong, Luo, Hongbo R., Bradner, James E., Tenen, Daniel G., Li Chai, and Chong Gao
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TRANSCRIPTION factors , *MYELOID leukemia , *LEUKEMIA etiology , *TUMOR suppressor proteins , *PHOSPHATASES , *HISTONE deacetylase , *RNA interference - Abstract
An exciting recent approach to targeting transcription factors in cancer is to block formation of oncogenic complexes. We investigated whether interfering with the interaction of the transcription factor SALL4, which is critical for leukemic cell survival, and its epigenetic partner complex represents a novel therapeutic approach. The mechanism of SALL4 in promoting leukemogenesis is at least in part mediated by its repression of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) through its interaction with a histone deacetylase (HDAC) complex. In this study, we demonstrate that a peptide can compete with SALL4 in interacting with the HDAC complex and reverse its effect on PTEN repression. Treating SALL4-expressing malignant cells with this peptide leads to cell death that can be rescued by a PTEN inhibitor. The antileukemic effect of this peptide can be confirmed on primary human leukemia cells in culture and in vivo, and is identical to that of down-regulation of SALL4 in these cells using an RNAi approach. In summary, our results demonstrate a novel peptide that can block the specific interaction between SALL4 and its epigenetic HDAC complex in regulating its target gene, PTEN. Furthermore, targeting SALL4 with this approach could be an innovative approach in treating leukemia. [ABSTRACT FROM AUTHOR]
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- 2013
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19. CUX1 is a haploinsufficient tumor suppressor gene on chromosome 7 frequently inactivated in acute myeloid leukemia.
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Karmakar, Subhradip, McNemey, Megan E., Brown, Christopher D., Xiaoyue Wang, Grossman, Robert L., Shan Yu, Bandlamudi, Chaitanya, Beau, Michelle M. Le, Anastasi, John, Bartom, Elizabeth T., Sandall, Barry P., Jinkyung Ko, Cunningham, John M., and Strieker, Thomas
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TUMOR suppressor proteins , *ACUTE erythroid leukemia , *HUMAN chromosomes , *BLOOD cells , *HEMATOPOIETIC growth factors , *SINGLE nucleotide polymorphisms , *DROSOPHILA melanogaster - Abstract
Loss of chromosome 7 and del(7q) [-7/del(7q)] are recurring cytogenetic abnormalities in hematologic malignancies, including acute myeloid leukemia and therapy-related myeloid neoplasms, and associated with an adverse prognosis. Despite intensive effort by many laboratories, the putative myeloid tumor suppressor(s) on chromosome 7 has not yet been identified. We performed transcriptome sequencing and SNP array analysis on de novo and therapy-related myeloid neoplasms, half with -7/del(7q). We identified a 2.17-Mb commonly deleted segment on chromosome band 7q22.1 containing CUX1, a gene encoding a homeodomain-containing transcription factor. In 1 case, CUX1 was disrupted by a translocation, resulting in a loss-of-function RNA fusion transcript. CUX1 was the most significantly differentially expressed gene within the commonly deleted segment and was expressed at haploinsufficient levels in -7/del(7q) leukemias. Haploinsufficiency of the highly conserved ortholog, cut, led to hemocyte overgrowth - and tumor formation in Drosophila melanogaster. Similarly, haploinsufficiency of CUX1 gave human hematopoietic cells a significant engraftment advantage on transplantation into immunodeficient mice. Within the RNA-sequencing data, we identified a CUXt-associated cell cycle transcriptional gene signature, suggesting that CUX1 exerts tumor suppressor activity by regulating proliferative genes. These data identify CUX1 as a conserved, haploinsufficient tumor suppressor frequently deleted in myeloid neoplasms. [ABSTRACT FROM AUTHOR]
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- 2013
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20. PU.1 is a potent tumor suppressor in classical Hodgkin lymphoma cells.
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Yuki, Hiromichi, Ueno, Shikiko, Tatetsu, Hiro, Niiro, Hiroaki, lino, Tadafumi, Endo, Shinya, Kawano, Yawara, Komohara, Yoshihiro, Takeya, Motohiro, Hata, Hiroyuki, Okada, Seiji, Watanabe, Toshiki, Akashi, Koichi, Mitsuya, Hiroaki, and Okuno, Yutaka
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TUMOR suppressor proteins , *HODGKIN'S disease , *HISTONE deacetylase inhibitors , *DISEASE remission , *GENETIC transduction , *DNA demethylation , *APOPTOSIS , *DNA microarrays , *VIRUSES - Abstract
PU.1 has previously been shown to be down-regulated in classical Hodgkin lymphoma (cHL) cells via promoter methylation. We performed bisulfite sequencing and proved that the promoter region and the -17 kb upstream regulatory element of the PU.1 gene were highly methylated. To evaluate whether down-regulation of PU.1 is essential for the growth of cHL cells, we conditionally expressed PU.1 in 2 cHL cefl lines, L428 and KM-H2. Overexpression of PU.1 induced complete growth arrest and apoptosis in both cell lines. Furthermore, in a Hodgkin lymphoma tumor xenograft model using L428 and KM-H2 cell lines, overexpression of PU.1 led to tumor regression or stable disease. Lentiviral transduction of PU.1 into primary cHL cells also induced apoptosis. DNA microarray analysis revealed that among genes related to cell cycle and apoptosis, p21 (CDKN1A) was highly up-regulated in L428 cells after PU.1 induction. Stable knockdown of p21 rescued PU.1-induced growth arrest in L428 cells, suggesting that the growth arrest and apoptosis observed are at least partially dependent on p21 up-regulation. These data strongly suggest that PU.1 is a potent tumor suppressor in cHL and that induction of PU.1 with demethylation agents and/or histone deacetylase inhibitors is worth exploring as a possible therapeutic option for patients with cHL. [ABSTRACT FROM AUTHOR]
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- 2013
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21. Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia.
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Lapalombella, Rosa, Sun, Qingxiang, Williams, Katie, Tangeman, Larissa, Jha, Shruti, Zhong, Yiming, Goettl, Virginia, Mahoney, Emilia, Berglund, Caroline, Gupta, Sneha, Farmer, Alicia, Mani, Rajeswaran, Johnson, Amy J., Lucas, David, Mo, Xiaokui, Daelemans, Dirk, Sandanayaka, Vincent, Shechter, Sharon, McCauley, Dilara, and Shacham, Sharon
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LYMPHOCYTIC leukemia , *CANCER , *TUMOR suppressor proteins , *CYSTEINE , *LEUKEMIA - Abstract
The nuclear export protein XPO1 is over-expressed in cancer, leading to the cyto-plasmic mislocalization of multiple tumor suppressor proteins. Existing XPO1-targeting agents lack selectivity and have been associated with significant toxicity. Small molecule selective inhibitors of nuclear export (SINEs) were designed that specifically inhibit XP01. Genetic experiments and X-ray structures demonstrate that SINE covalently bind to a cysteine residue in the cargo-binding groove of XPO1, thereby inhibiting nuclear export of cargo proteins. The clinical relevance of SINEs was explored in chronic lympho cytic leukemia (CLL), a disease associated with recurrent XPO1 mutations. Evidence is presented that SINEs can restore normal regulation to the majority of the dysregulated pathways in CLL both in vitro and in vivo and induce apoptosls of CLL cells with a favorable therapeutic index, with enhanced killing of genomically high-risk CLL cells that are typically unresponsive to traditional therapies. More importantly, SINE slows disease progression, and improves overall survival In the Eμ-TCL1-SCID mouse model of CLL with minimal weight loss or other toxicities. Together, these findings demonstrate that XPO1 is a valid target in CLL with minimal effects on normal cells and provide a basis for the development of SINEs in CLL and related hematologic malignancies. [ABSTRACT FROM AUTHOR]
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- 2012
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22. Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP: report from an International DLBCL Rituximab-CHOP Consortium Program Study.
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Xu-Monette, Zljun Y., Lin Wu, Carlo Visco, Yu Chuan Tai, Tzankov, Alexander, Wel-min Liu, Santiago Montes-Moreno, Dybkasr, Karen, April Chiù, Attilio Orazi, Youli Zu, Govind Bhagat, Richards, Kristy L., Eric D. Hsi, Zhao, X. Frank, Choi, William W. L., Xiaoying Zhao, van Krieken, J. Han, Qin Huang, and Jooryung Huh
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B cell lymphoma , *GENETIC mutation , *TUMOR suppressor proteins , *RITUXIMAB , *DNA-binding proteins , *IMMUNOHISTOCHEMISTRY , *CYCLOPHOSPHAMIDE , *DOXORUBICIN , *VINCRISTINE , *PATIENTS - Abstract
TP53 mutation is an independent marker of poor prognosis in patients with diffuse large B-cell lymphoma (DLBCL) treated with cyclophosphamide, hydroxydauno-rubicin, vincristine, and prednisone (CHOP) therapy. However, its prognostic value in the rituximab immunochemo-therapy era remains undefined. In the present study of a large cohort of DLBCL patients treated with rituximab plus CHOP (R-CHOP), we show that those with TP53 mutations had worse overall and progression-free survival compared with those without. Unlike earlier studies of patients treated with CHOP, TP53 mutation has predictive value for R-CHOP-treated patients with either the germinal center B-cell or activated B-cell DLBCL subtypes. Furthermore, we Identified the loop-sheet-helix and L3 motifs in the DNA-blnding domain to be the most critical structures for maintaining p53 function. In contrast, TP53 deletion and loss of heterozygosity did not confer worse survival. If gene mutation data are not available, immunohlstochemlcal analysis showing > 50% cells expressing p53 protein is a useful surrogate and was able to stratify patients with significantly different prognoses. We conclude that assessment of TP53 mutation status is important for stratifying R-CHOP-treated patients into distinct prognostic subsets and has significant value in the design of future therapeutic strategies. [ABSTRACT FROM AUTHOR]
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- 2012
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23. Preclinical activity of a novel CRMl inhibitor in acute myeloid leukemia.
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Ranganathan, Parvathi, Yu, Xueyan, Na, Caroline, Santhanam, Ramasamy, Shacham, Sharon, Kauffman, Michael, Walker, Alison, Klisovic, Rebecca, Blum, William, Caligiuri, Michael, Croce, Carlo M., Marcucci, Guido, and Garzon, Ramiro
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MEDICAL sciences , *ACUTE myeloid leukemia , *CHROMOSOME abnormalities , *NUCLEAR proteins , *TUMOR suppressor proteins , *NUCLEOPHOSMIN , *P53 antioncogene - Abstract
Chromosome maintenance protein 1 (CRIV11) is a nuclear export receptor involved in the active transport of tumor suppressors (eg, p53 and nucleophosmin) whose function is altered in cancer because of increased expression and overactive transport. Blocking CRMI-mediated nuclear export of such proteins is a novel therapeutic strategy to restore tumor suppressor function. Orally bioavailable selective inhibitors of nuclear export (SINE) that irreversibly bind to CRIV11 and block the function of this protein have been réintroduction cently developed. Here we investigated the antileukemic activity of KPT-SINE (KPT-185 and KPT-276) in vitro and in vivo in acute myeloid leukemia (AML). KPT- 185 displayed potent antiproliferative properties at submicromolar concentrations (IC50 values; 100-500nM), induced apoptosis (average 5-fold increase), cellcycle arrest, and myeloid differentiation in AIVIL cell lines and patient blasts. A strong down-regulation of the oncogene FLT3 after KPT treatment in both FLT3- ITD and wild-type cell lines was observed. Finally, using the FLTS-ITD-positive MV4-11 xenograft murine model, we show that treatment of mice with oral KPT- 276 (analog of KPT-185 for in vivo studies) significantly prolongs survival of leukemic mice (P<.01). In summary, KPT-SINE are highly potent in vitro and in vivo in AML. The preclinical results reported here support clinical trials of KPTSINE in AML. [ABSTRACT FROM AUTHOR]
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- 2012
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24. Cell transformation by FLT3ITD in acute myeloid leukemia involves oxidative inactivation of the tumor suppressor protein-tyrosine phosphatase DEP-1/ PTPRJ.
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Godfrey, Rinesh, Arora, Deepika, Bauer, Reinhard, Stopp, Sabine, Müller, Jörg P., Heinrich, Theresa, Böhmer, Sylvia-Annette, Dagnell, Markus, Schnetzke, Ulf, Scholl, Sebastian, Östman, Arne, and Böhmer, Frank-D.
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ACUTE myeloid leukemia , *TUMOR suppressor proteins , *PROTEIN-tyrosine phosphatase , *CELLULAR signal transduction , *REACTIVE oxygen species , *CATALASE , *NADPH oxidase - Abstract
Signal transductio n of FMS-like tyrosine kinase 3 (FLT3) is regulated by protein-tyrosine phosphatases (PTPs). We recently identified the PTP DEP-1/CD148/ PTPRJ as a novel negative regulator of FLT3. This study addressed the role of DEP-1 for regulation of the acute myeloid leukemia (AML)-related mutant FLT3 internal tandem duplication (ITD) protein. Our experiments revealed that DEP-1 was expressed but dysfunctional in cells transformed by FLT3 ITD. This was caused by enzymatic inactivation of DEP-1 through oxidation of the DEP-1 catalytic cysteine. In intact cells, including primary AML cells, FLT3 ITD kinase inhibition reactivated DEP-1. DEP-1 reactivation was also achieved by counteracting the high levels of reactive oxygen species (ROS) production detected in FLT3 ITD-expressing cell lines by inhibition of reduced NAD phosphate (NADPH)-oxidases, or by overex-pression of catalase or peroxiredoxin-1 (Prx-1). Interference with ROS production in 32D cells inhibited cell transformation by FLT3 ITD in a DEP-1-dependent manner because RNAi-mediated depletion of DEP-1 partially abrogated the inhibitory effect of ROS quenching. Reactivation of DEP-1 by stable overexpression of Prx-1 extended survival of mice in the 32D cell/C3H/HeJ mouse model of FLT3 ITD-driven myeloproliferative disease. The study thus uncovered DEP-1 oxidation as a novel event contributing to cell transformation by FLT3 ITD [ABSTRACT FROM AUTHOR]
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- 2012
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25. FOXOl is a tumor suppressor in classical Hodgkin lymphoma.
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Xie, Linka, Ushmorov, Alexey, Leithäuser, Frank, Guan, Hanfeng, Steidl, Christian, Färbinger, Johanna, Pelzer, Christin, Vogel, Marion J., Maier, Harald J., Gascoyne, Randy D., Möller, Peter, and Wirth, Thomas
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TRANSCRIPTION factors , *TUMOR suppressor proteins , *HODGKIN'S disease , *APOPTOSIS , *CELL proliferation , *B cell lymphoma , *MITOGEN-activated protein kinases , *MICRORNA , *LYMPHOMAS - Abstract
The FOXO transcription factors control proliferation and apoptosis in different cell types. Their activity is regulated by posttranslational modifications, mainly by the PI3K-PKB pathway, which controls nuclear export and degradation. We show that FOXOl is highly expressed in normal germinal center B cells as well as in non-Hodgkin lymphomas, including follicular lymphoma, diffuse large B-cell lymphoma, mucosa-associated lymphoid tissue non-Hodgkin lymphoma, B-cell chronic lymphocytic leukemia, and mantle cell lymphoma. In contrast, in 31 of 32 classical Hodgkin lymphoma (cHL) cases, Hodgkin and Reed-Sternberg cells were FOX01 negative. Neoplastic cells of nodular lymphocyte-predominant Hodgkin lymphoma were negative in 14 of 20 cases. FOX01 was down-regulated in cHL cell lines, whereas it was expressed in non-Hodgkin lymphoma cell lines at levels comparable with normal B cells. Ectopic expression of a constitutively active FOXOl induced apoptosis in cHL cell lines and blocked proliferation, accompanied with cell-cycle arrest in the G0/G, phase. We found that, in cHL cell lines, FOX01 is inactivated by multiple mechanisms, including constitutive activation of AKT/PKB and MAPK/ERK kinases and up-regulation of microRNAs miR-96, miR-182, and miR-183. These results suggest that FOX01 repression contributes to cHL lymphomagenesis. [ABSTRACT FROM AUTHOR]
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- 2012
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26. TP 53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome.
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Rücker, Frank G., Schlenk, Richard F., Bullinger, Lars, Kayser, Sabine, Teleanu, Veronica, Kett, Helena, Habdank, Marianne, Kugler, Carla-Maria, Holzmann, Karlheinz, Gaidzik, Verena I., Paschka, Peter, Held, Gerhard, von Lilienfeld-Toal, Marie, Lübbert, Michael, Fröhling, Stefan, Zenz, Thorsten, Krauter, Jürgen, Schlegelberger, Brigitte, Ganser, Arnold, and Lichter, Peter
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ACUTE myeloid leukemia , *TUMOR suppressor proteins , *KARYOTYPES , *GENETIC mutation , *DISEASE remission , *HEALTH outcome assessment - Abstract
To assess the frequency of TP53 alterations and their correlation with other genetic changes and outcome in acute myeloid leukemia with complex karyotype (CK-AML), we performed integrative analysis using TP53 mutational screening and array-based genomic profiling in 234 CK-AMLs. TP53 mutations were found in 141 of 234 (60%) and TP53 losses were identified in 94 of 234 (40%) CK-AMLs; in total, 164 of 234 (70%) cases had TP53 alterations. 7P53-altered CK-AML were characterized by a higher degree of genomic complexity (aberrations per case, 14.30 vs 6.16; P< .0001) and by a higher frequency of specific copy number alterations, such as -5/5q-, -7/7q-, -16/ 16q-, -18/18q-, +1/+1p, and +11/+11q/ amp11q13∼25; among CK-AMLs, TP53-altered more frequently exhibited a monosomal karyotype (MK). Patients with TP53 alterations were older and had significantly lower complete remission rates, inferior event-free, relapse-free, and overall survival. In multivariable analysis for overall survival, TP53 alterations, white blood cell counts, and age were the only significant factors. In conclusion, TP53 is the most frequently known altered gene in CK-AML. TP53 alterations are associated with older age, genomic complexity, specific DNA copy number alterations, MK, and dismal outcome. In multivariable analysis, TP53 alteration is the most important prognostic factor in CK-AML, outweighing all other variables, including the MK category [ABSTRACT FROM AUTHOR]
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- 2012
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27. AP-1 elements and TCL1 protein regulate expression of the gene encoding protein tyrosine phosphatase PTPROt in leukemia.
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Motiwala, Tasneem, Zanesi, Nicola, Datta, Jharna, Roy, Satavisha, Kutay, Huban, Checovich, Allyn M., Kaou, Mohamed, Zhong, Yiming, Johnson, Amy J., Lucas, David M., Heerema, Nyla A., Hagan, John, Mo, Xiaokui, Jarjoura, David, Byrd, John C., Croce, Carlo M., and Jacob, Sand Samson T.
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PROTEIN-tyrosine phosphatase , *LEUKEMIA , *HEMATOPOIETIC growth factors , *TUMOR suppressor proteins , *LYMPHOCYTIC leukemia , *LEUKEMIA treatment - Abstract
We previously demonstrated that the gene encoding PTPROt, the truncated form of protein tyrosine phosphatase receptor type O expressed predominantly in hematopoietic cells, is a candidate tumor suppressor and is down-regulated in chronic lymphocytic leukemia (CLL). Here, we show that PTPROf expression is significantly reduced in CD19+ spleen B cells from Eμ-T cell leukemia 1 (TCL1) transgenic mice relative to the wild-type mice. Strikingly, as much as a 60% decrease in PTPROt expression occurs at 7 weeks independently of promoter methylation. To elucidate the potential mechanism for this early suppression of PTPROtin these mice, we explored the role of activating protein-i (AP-1) in its expression. We first demonstrate that AP-1 activation by 12-O-tetradecanoylphorbol-13-acetate induces PTPROt expression with concurrent recruitment of c-fos and c-jun to its promoter. The PTPROt promoter is also responsive to over-and underexpression of AP-1, confirming the role of AP-1 in PT-PROt expression. Next, we demonstrate that TCL1 can repress the PTPROt promoter by altering c-fos expression and c-jun activation state. Finally, using primary CLL cells we have shown an inverse relationship between TCL1 and PTPROt expression. These findings further substantiate the role of TCL1 in PTPROt suppression and its importance in the pathogenesis of CLL. [ABSTRACT FROM AUTHOR]
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- 2011
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28. The BCL11B tumor suppressor is mutated across the major molecular subtypes of T-cell acute lymphoblastic leukemia.
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Gutierrez, Alejandro, Kentsis, Alex, Sanda, Takaomi, Holmfeldt, Linda, Shann-Ching Chen, Jianhua Zhang, Protopopov, Alexei, Chin, Lynda, Dahlberg, Suzanne E., Neuberg, Donna S., Silverman, Lewis B., Winter, Stuart S., Hunger, Stephen P., Sallan, Stephen E., Shan Zha, Alt, Frederick W., Downing, James R., Mullighan, Charles G., and Look, A. Thomas
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TUMOR suppressor genes , *TUMOR suppressor proteins , *LYMPHOBLASTIC leukemia , *LEUKEMIA , *T cells , *CARCINOGENESIS - Abstract
The BCL11B transcription factor is required for normal T-cell development, and has recently been implicated in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) induced by TLX overexpression or Atm deficiency. To comprehensively assess the contribution of BCL11B inactivation to human T-ALL, we performed DNA copy number and sequencing analyses of T-ALL diagnostic specimens, revealing monoallelic BCL11B deletions or missense mutations in 9% (n = 10 of 117) of cases. Structural homology modeling revealed that several of the BCL11B mutations disrupted the structure of zinc finger domains required for this transcription factor to bind DNA. BCL11B haploinsufficiency occurred across each of the major molecular subtypes of T-ALL, including early T-cell precursor, HOXA-positive, LEF1-inactivated, and TAL1-positive subtypes, which have differentiation arrest at diverse stages of thymocyte development. Our findings provide compelling evidence that BCL11B is a haploinsufficient tumor suppressor that collaborates with all major T-ALL oncogenic lesions in human thymocyte transformation. [ABSTRACT FROM AUTHOR]
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- 2011
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29. SET oncoprotein overexpression in B-cell chronic lymphocytic leukemia and non-Hodgkin lymphoma: a predictor of aggressive disease and a new treatment target.
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Christensen, Dale J., Youwei Chen, Oddo, Jessica, Matta, Karen M., Neil, Jessica, Davis, Evan D., Volkheimer, Alicia D., Lanasa, Mark C., Friedman, Daphne R., Goodman, Barbara K., Gockerman, Jon P., Diehl, Louis F., de Castro, Carlos M., Moore, Joseph O., Vitek, Michael P., and Weinberg, J. Brice
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B cells , *CHRONIC lymphocytic leukemia , *LYMPHOMAS , *APOPTOSIS , *PHOSPHOPROTEIN phosphatases , *TUMOR suppressor proteins , *XENOGRAFTS , *LABORATORY mice - Abstract
B-cell chronic lymphocytic leukemia (CLL), an incurable leukemia, is characterized by defective apoptosis. We found that the SET oncoprotein, a potent inhibitor of the protein phosphatase 2A (PP2A) tumor suppressor, is overexpressed in primary CLL cells and B-cell non-Hodgkin lymphoma (NHL) cell line cells. In CLL, increased levels of SET correlated significantly with disease severity (shorter time to treatment and overall survival). We developed SET antagonist peptides that bound SET, increased cellular PP2A activity, decreased Mcl-1 expression, and displayed selective cytotoxicity for CLL and NHL cells in vitro. In addition, shRNA for SET was cytotoxic for NHL cells in vitro. The SET antagonist peptide COG449 inhibited growth of NHL tumor xenografts in mice. These data demonstrate that SET is a new treatment target in B-cell malignancies and that SET antagonists represent novel agents for treatment of CLL and NHL. [ABSTRACT FROM AUTHOR]
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- 2011
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30. RNA-sequencing analysis of core binding factor AML identifies recurrent ZBTB7A mutations and defines RUNX1-CBFA2T3 fusion signature
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Vincent-Philippe Lavallée, Geneviève Boucher, Josée Hébert, Richard Neil Armstrong, Isabel Boivin, Patrick Gendron, Guy Sauvageau, and Sébastien Lemieux
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Adult ,Male ,0301 basic medicine ,Adolescent ,Oncogene Proteins, Fusion ,Immunology ,Repressor ,Transcription factor complex ,Biology ,Core binding factor ,Biochemistry ,Cohort Studies ,Young Adult ,03 medical and health sciences ,chemistry.chemical_compound ,hemic and lymphatic diseases ,Humans ,Gene ,Transcription factor ,Aged ,Aged, 80 and over ,Genetics ,Tumor Suppressor Proteins ,RNA ,Myeloid leukemia ,Cell Biology ,Hematology ,Middle Aged ,DNA-Binding Proteins ,Repressor Proteins ,Leukemia, Myeloid, Acute ,030104 developmental biology ,RUNX1 ,chemistry ,Core Binding Factor Alpha 2 Subunit ,Mutation ,Female ,Transcriptome ,Transcription Factors - Abstract
To the editor: RUNX1 (also known as AML1 or CBFA2 ) and CBFB encode the α and β subunits of a heterodimeric core binding transcription factor complex involved in the development of normal hematopoiesis (reviewed by de Bruijn and Speck[1][1]). Both genes are rearranged in acute myeloid leukemia (
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- 2016
31. Influence of Cytogenetics in Patients with Relapsed Refractory Multiple Myeloma Treated with Oral Selinexor and Dexamethasone: A Post-Hoc Analysis of the STORM Study
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Andrew Yee, Joshua Richter, Anita Joshi, David S. Siegel, Jianjun Liu, David Dingli, Sharon Shacham, Meletios A. Dimopoulos, Maria Gavriatopoulou, Carol Ann Huff, Jatin P. Shah, Sundar Jagannath, Ravi Vij, Marc S. Raab, Paul G. Richardson, Ajai Chari, Sascha A. Tuchman, Noa Biran, Philippe Moreau, Dan T. Vogl, Craig E. Cole, Ajay K. Nooka, Sagar Lonial, and Michael Kauffman
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Oncology ,medicine.medical_specialty ,business.industry ,education ,Immunology ,Complete remission ,Cytogenetics ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Tumor suppressor proteins ,Internal medicine ,Post-hoc analysis ,Relapsed refractory ,medicine ,In patient ,business ,health care economics and organizations ,Multiple myeloma ,Dexamethasone ,medicine.drug - Abstract
Introduction: Selinexor is a novel, oral selective inhibitor of nuclear export (SINE) which forces nuclear retention and activation of tumor suppressor proteins. Selinexor plus low dose dexamethasone (Sel-dex) was recently approved in the United States based on data from the STORM study wherein, Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma. The presence of high-risk cytogenetic abnormalities is known to have a poor prognosis in multiple myeloma, with transient responses. We performed post-hoc analyses to determine the outcomes in patients with relapsed/refractory myeloma treated with Sel-dex based on the baseline cytogenetic abnormalities. Methods: STORM was a phase 2b, open-label study which enrolled patients with relapsed and refractory myeloma. Selinexor 80 mg in combination with dexamethasone 20 mg was administered orally, twice weekly. The primary endpoint was ORR. For this analysis, we pooled 78 patients (48 quad-refractory and 30 penta-refractory) from STORM, part 1 and 122 patients (penta-exposed and triple class refractory) from STORM, part 2 to compare outcomes between high-risk and standard risk cytogenetics groups. High-risk cytogenetics was defined as having at least 1 of the following abnormalities by fluorescence in-situ hybridization (FISH) at baseline: del(17p), t(4;14), t(14;16), and gain(1q) in >5% of screened plasma cells. The FISH analyses were performed at a central laboratory and used to assess cytogenetic risk status. Results: Of the 200 patients, 122 (61%) had high-risk disease (del(17p): 36%, t(4;14): 18%, t(14;16): 5%, and gain(1q): 36%). The ORR in high-risk patients was 20.5% (very good partial response [VGPR)]: 5.7% and partial response [PR]: 14.8%) and the ORR was 29.5 % (complete response [CR]: 2.6%, VGPR: 3.8%, and PR: 23.1%) in standard-risk patients. The clinical benefit rate (CBR) was 35.2% in high-risk patients compared with 38.5% in standard-risk patients. Median duration of clinical benefit (DOCB) was 4.4 and 6.2 months in the high-risk and standard-risk patients respectively. Median progression-free survival (PFS) was 3.8 and 4.2 months and overall survival (OS) was 8.6 and 9.4 months in the high-risk and standard-risk patients, respectively. Efficacy by specific cytogenetic abnormality is presented in Table 1 below (Due to the small sample size (n=11), data for the t(14;16) subgroup are not presented separately). Conclusions: Sel-dex demonstrated a similar CBR in patients with high risk and standard risk disease and preserved clinical benefit in heavily pre-treated patients who had rapidly proliferative disease and high-risk cytogenetics at baseline. The benefit was maintained across cytogenetic risk subgroups with a higher ORR in the t(4;14) and gain(1q) subgroups. The DOR and OS was similar across all the subgroups. These analyses support the use of Sel-dex in patients with high-risk cytogenetics and warrant further evaluation of selinexor in combination with other anti-myeloma therapies in high-risk disease. Disclosures Nooka: GSK: Honoraria, Other: advisory board participation; Amgen: Honoraria, Other: advisory board participation; BMS: Honoraria, Other: advisory board participation; Janssen: Honoraria, Other: advisory board participation; Spectrum pharmaceuticals: Honoraria, Other: advisory board participation; Adaptive technologies: Honoraria, Other: advisory board participation; Celgene: Honoraria, Other: advisory board participation; Takeda: Honoraria, Other: advisory board participation. Yee:Adaptive: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Huff:Karyopharm, Sanofi, MiDiagnostics: Consultancy; Member of Safety Monitoring Board for Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees. Vogl:Karyopharm Therapeutics: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Active Biotech: Consultancy. Chari:Novartis Pharmaceuticals: Research Funding; GlaxoSmithKline: Research Funding; Array Biopharma: Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Oncoceutics: Research Funding. Moreau:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; Millenium: Consultancy; alexion: Consultancy; Janssen: Consultancy. Lonial:Genentech: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy; BMS: Consultancy; Janssen: Consultancy, Research Funding; GSK: Consultancy; Celgene Corporation: Consultancy, Research Funding. Dimopoulos:Sanofi Oncology: Research Funding. Vij:Takeda: Honoraria, Research Funding; Sanofi: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; Genentech: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Tuchman:Karyopharm: Honoraria; Celgene: Honoraria, Research Funding, Speakers Bureau; Amgen: Research Funding; Merck: Research Funding; Prothena: Research Funding; Roche: Research Funding; Sanofi: Research Funding; Alnylam: Honoraria, Research Funding. Biran:Bristol Meyers Squibb: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Siegel:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Richardson:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Liu:Karyopharm Therapeutics: Employment, Equity Ownership. Joshi:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Jagannath:Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau; BMS: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Merck: Consultancy.
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- 2019
32. A Phase 1b/2 Study of Selinexor, Carfilzomib, and Dexamethasone (SKd) in Relapsed/ Refractory Multiple Myeloma (RRMM)
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Nizar J. Bahlis, Jatin P. Shah, Brea Lipe, Michael Sebag, Richard Leblanc, Christine Chen, Yi Chai, Suzanne Lentzsch, Sascha A. Tuchman, Muhamed Baljevic, Heather J. Sutherland, William I. Bensinger, Cristina Gasparetto, Christopher P. Venner, Natalie S. Callander, Rami Kotb, Sharon Shacham, Heidi Sheehan, Michael Kauffman, Darrell White, Gary J. Schiller, and Kazuharu Kai
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Dose limiting toxicity ,business.industry ,Immunology ,Cell Biology ,Hematology ,Pomalidomide ,Biochemistry ,Carfilzomib ,03 medical and health sciences ,Tumor suppressor proteins ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,Partial response ,Maximum tolerated dose ,Family medicine ,Relapsed refractory ,medicine ,Bristol myer squibb ,business ,030215 immunology ,medicine.drug - Abstract
Introduction: Selinexor is a novel, first-in-class selective inhibitor of nuclear export (SINE), which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins. Selinexor in combination with low dose dexamethasone (Sel-dex) was recently approved based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma (MM). The recommended phase 2 dose (RP2D) of twice-weekly combination of selinexor, carfilzomib, and dexamethasone (SKd) was selinexor 60 mg, carfilzomib 20/27 mg/m2 and dexamethasone 20 mg (NCT02199665). The ORR of this regimen in patients with MM refractory to carfilzomib in last line of therapy (n=13) was 62% and clinical benefit response was 77% (Jakubowiak et al. Br J Haematol 2019). This is consistent with data from the combination of selinexor, bortezomib and dexamethasone where a 43% ORR was observed in bortezomib refractory disease. We conducted the STOMP study to assess the safety and preliminary efficacy of SKd combination using once weekly (QW) dosing in patients with relapsed/refractory MM. Methods: STOMP is a multicenter, open-label study. Patients with relapsed/refractory MM that was not refractory to carfilzomib, and who may have had prior proteasome inhibitor exposure were enrolled. Oral Selinexor was dosed QW at 80 or 100 mg. Carfilzomib was dosed QW (excluding day 22 of 28-day cycle) at 56 mg/m2 or 70 mg/m2. Dexamethasone was dosed at 40 mg QW. The primary objectives of the study are to assess the maximum tolerated dose, RP2D and evaluate the efficacy and safety of SKd in patients with relapsed/refractory MM. Results: As of July 01 2019, 12 patients were enrolled in the study. Of these, 5 were male and 7 were female. The median age was 70 years (range: 50-76 years). The median number of prior treatments was 4 (range: 2 - 8). Nine of 12 patients received prior autologous stem cell transplantation. All 12 patients were carfilzomib naïve. Nine of 12 patients had MM refractory to bortezomib; 11 patients had MM refractory to lenalidomide and/or pomalidomide including 5 patients with MM refractory to both; and 7 patients with MM refractory to daratumumab. Four dose limiting toxicities (DLTs) were observed across 3 dose cohorts (Table 1). Common treatment related adverse events (Grade 1/2 , Grade ≥3) included anemia (42%, 17%), thrombocytopenia (17%, 58%), leukopenia (17%, 17%), nausea (67%, 0%), decreased appetite (33%, 0%), insomnia (33%, 0%), hyperglycemia (25%, 17%), fatigue (25%, 8%), vomiting (25%, 8%), and pneumonia (0%, 17%). The ORR was 75% including 3 complete responses, 5 very good partial responses and 1 partial response. Two patients had stable disease and 1 patient had minimal response. As of July 01, 8 patients remain on treatment. Conclusions: The once weekly SKd combination demonstrated encouraging preliminary activity with an ORR of 75% including complete responses and very good partial responses. Most DLTs were thrombocytopenia and all the DLT events occurred in patients with baseline Grade 1/2 thrombocytopenia. This activity and manageable side effect profile with QW selinexor in combination with carfilzomib and dexamethasone is promising. Disclosures Gasparetto: Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Schiller:Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Agios: Research Funding, Speakers Bureau; Amgen: Other, Research Funding; Constellation Pharmaceutical: Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau. Lentzsch:Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy. Tuchman:Roche: Research Funding; Alnylam: Honoraria, Research Funding; Karyopharm: Honoraria; Prothena: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; Amgen: Research Funding; Sanofi: Research Funding; Merck: Research Funding. Bahlis:Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. White:Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Chen:Amgen: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Baljevic:Cardinal Health Specialty Solutions: Consultancy; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Other: Internal Review Committee participant. Kotb:Takeda: Honoraria; Amgen: Honoraria; Merck: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria; Karyopharm: Equity Ownership. Leblanc:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sebag:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Venner:Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria, Research Funding; J&J: Research Funding; Sanofi: Honoraria; Takeda: Honoraria. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant. Sheehan:Karyopharm Therapeutics: Employment, Equity Ownership. Chai:Karyopharm Therapeutics: Employment, Equity Ownership. Kai:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Lipe:Celgene: Consultancy; amgen: Consultancy; amgen: Research Funding.
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- 2019
33. A Machine Learning Approach Identifies a 30-Gene Model That Predicts Sensitivity to Selinexor in Multiple Myeloma
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Joel T. Dudley, Samir Parekh, Sundar Jagannath, Sherry Bhalla, Alessandro Laganà, Itai Beno, Hearn Jay Cho, Adolfo Aleman, Ajai Chari, Yosef Landesman, Violetta V. Leshchenko, Joshua Richter, David Melnekoff, Anna Huo-Chang Mei, and Deepu Madduri
- Subjects
Computer science ,business.industry ,Gene model ,Bortezomib ,education ,Immunology ,Daratumumab ,Cell Biology ,Hematology ,Machine learning ,computer.software_genre ,medicine.disease ,Pomalidomide ,Biochemistry ,Tumor suppressor proteins ,medicine ,Artificial intelligence ,Sensitivity (control systems) ,business ,Area under the roc curve ,computer ,health care economics and organizations ,Multiple myeloma ,medicine.drug - Abstract
Selinexor is the first FDA-approved drug for penta-refractory multiple myeloma (MM) patients, i.e. patients refractory to at least two proteasome inhibitors, two immunomodulatory drugs, and an anti-CD38 monoclonal antibody. Selinexor is an oral selective inhibitor of nuclear export (SINE), which specifically targets XPO1 (Exportin 1)-mediated nuclear export, leading to increased nuclear accumulation and activation of major tumor suppressor proteins, inhibition of NF-kB, and inducing selective apoptosis in cancer cells. Several phase I and II clinical trials demonstrated evidence of anti-cancer activity of Selinexor in solid tumors, non-Hodgkin lymphoma, acute myeloid leukemia and MM (PMIDs: 29487219, 27458288, 28647672, 28468797, 29304833, 29381435). In the pivotal phase 2b STORM (Selinexor Treatment of Refractory Myeloma) trial, the combination of Selinexor with dexamethasone in patients with MM treated with prior bortezomib, carfilzomib, lenalidomide, pomalidomide and daratumumab (penta-exposed) and triple class refractory MM, has shown an overall response rate (ORR) of 26.2% and a clinical benefit rate of 39.3%, with a median progression-free survival (PFS) of 3.7 months and median overall survival (OR) of 8.6 months (Chari et al, NEJM in press 2019). In order to identify biomarkers for selection of patients at higher likelihood of clinical benefit from Selinexor therapy and understand mechanisms of Selinexor resistance, we analyzed the transcriptome of CD138+ cells from bone marrow aspirates obtained prior to treatment from 54 patients enrolled in STORM. The raw data (fastq) was mapped using the tool STAR and gene-level annotated using the tool featureCounts. Gene expression counts were normalized using the variance stabilization transformation (VST) method implemented in the tool DESeq2, including potential confounding variables such as sequencing batch as covariates. Patients were split in two groups based on PFS = 120 days. We trained a linear Support Vector Machine (SVM) with L1 regularization to select features discriminating between responders (PFS > 120, n = 17) and non-responders (PFS < 120, n = 37). The L1 regularization reduces data dimensionality in large dataset and enables selection of the most relevant features. We trained the SVM using 80% (43) of the samples for feature selection and training with leave-one-out cross validation, and the remaining 20% (11) for model testing. The SVM achieved an AUC (Area Under ROC Curve) value of 0.71 on the test set. The model consisted of 30 genes which identified 3 patient clusters with significantly different PFS (Fig 1a, 1b). The cluster with poorer PFS was characterized by up-regulation of MAGE-A1. MAGE-A is a cancer testis antigen that is aberrantly expressed in MM (PMID: 21565982) and has recently been described to have a critical role in chemotherapy resistance via regulation of BIM and p53 (Chari et al, Blood Advances 2017; Cho et al, ASH 2018). To test whether MAGE-A may contribute mechanistically to Selinexor resistance, we treated MM cells (H929 and RPMI8226) with Selinexor after depletion of MAGE-A by RNA interference. Our results show decreased viability in MAGE-A depleted cells as compared to non-target siRNA, suggesting that MAGE-A depletion increases sensitivity to Selinexor. Taken together, our results provide a signature for selecting patients that may benefit from Selinexor therapy and provide insights into mechanisms of Selinexor resistance. We are currently performing whole-exome sequencing profiling of the patients in this study and will present the results at ASH 2019. Disclosures Landesman: Karyopharm Therapeutics Inc: Employment. Madduri:undation Medicine: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Abbvie: Consultancy. Richter:Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Speakers Bureau; Bristol-Meyers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Chari:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; GlaxoSmithKline: Research Funding; Novartis Pharmaceuticals: Research Funding; Oncoceutics: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Cho:BMS: Consultancy; The Multiple Myeloma Research Foundation: Employment; Takeda: Research Funding; GSK: Consultancy; Celgene: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Agenus: Research Funding. Jagannath:BMS: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Merck: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau. Parekh:Karyopharm Inc.: Research Funding; Foundation Medicine Inc.: Consultancy; Celgene Corporation: Research Funding.
- Published
- 2019
34. The antiphospholipid syndrome finally fathomed?
- Author
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Philip G. de Groot
- Subjects
0301 basic medicine ,Immunology ,Plenary Paper ,030204 cardiovascular system & hematology ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Antiphospholipid syndrome ,Medicine ,Humans ,Endothelium ,Adaptor Proteins, Signal Transducing ,chemistry.chemical_classification ,business.industry ,Tumor Suppressor Proteins ,Thrombosis ,Cell Biology ,Hematology ,medicine.disease ,Antiphospholipid Syndrome ,030104 developmental biology ,chemistry ,Antibodies, Antiphospholipid ,Glycoprotein ,business ,Apoptosis Regulatory Proteins ,Glycoprotein i - Abstract
In the antiphospholipid syndrome (APS), antiphospholipid antibody (aPL) recognition of β2 glycoprotein I promotes thrombosis, and preclinical studies indicate that this is due to endothelial nitric oxide synthase (eNOS) antagonism via apolipoprotein E receptor 2 (apoER2)-dependent processes. How apoER2 molecularly links these events is unknown. Here, we show that, in endothelial cells, the apoER2 cytoplasmic tail serves as a scaffold for aPL-induced assembly and activation of the heterotrimeric protein phosphatase 2A (PP2A). Disabled-2 (Dab2) recruitment to the apoER2 NPXY motif promotes the activating L309 methylation of the PP2A catalytic subunit by leucine methyl transferase-1. Concurrently, Src homology domain-containing transforming protein 1 (SHC1) recruits the PP2A scaffolding subunit to the proline-rich apoER2 C terminus along with 2 distinct regulatory PP2A subunits that mediate inhibitory dephosphorylation of Akt and eNOS. In mice, the coupling of these processes in endothelium is demonstrated to underlie aPL-invoked thrombosis. By elucidating these intricacies in the pathogenesis of APS-related thrombosis, numerous potential new therapeutic targets have been identified.
- Published
- 2018
35. Tyrosine kinase inhibitor–induced defects in DNA repair sensitize FLT3(ITD)-positive leukemia cells to PARP1 inhibitors
- Author
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Margaret Nieborowska-Skorska, Jaroslav Jelinek, Katarzyna Piwocka, Elizaveta A. Belyaeva, Alina Nersesyan, Zhaorui Lian, Peter Valent, Lars Bullinger, Paulina Podszywalow-Bartnicka, Nicolas Chatain, Tomasz Sliwinski, Małgorzata Rydzanicz, Bac Viet Le, Tomasz Stoklosa, Monika Toma, Mariusz A. Wasik, Steffen Koschmieder, Thomas Fischer, Martyna Solecka, Stephen M. Sykes, Tomasz Skorski, Katherine Sullivan-Reed, Rafał Płoski, Yashodhara Dasgupta, Huaqing Zhao, Silvia Maifrede, Jian Huang, and Marcin M Machnicki
- Subjects
0301 basic medicine ,Myeloid ,DNA Repair ,Poly (ADP-Ribose) Polymerase-1 ,Synthetic lethality ,Biochemistry ,Tyrosine-kinase inhibitor ,Piperazines ,chemistry.chemical_compound ,DNA Ligase ATP ,Mice ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Myeloid Neoplasia ,BRCA1 Protein ,Myeloid leukemia ,hemic and immune systems ,Hematology ,3. Good health ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,embryonic structures ,Stem cell ,Fanconi Anemia Complementation Group N Protein ,psychological phenomena and processes ,DNA repair ,medicine.drug_class ,Immunology ,Olaparib ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Benzothiazoles ,Protein Kinase Inhibitors ,BRCA2 Protein ,business.industry ,Phenylurea Compounds ,Tumor Suppressor Proteins ,Cell Biology ,medicine.disease ,Xenograft Model Antitumor Assays ,030104 developmental biology ,chemistry ,fms-Like Tyrosine Kinase 3 ,Mutation ,Cancer research ,Phthalazines ,Rad51 Recombinase ,business - Abstract
Mutations in FMS-like tyrosine kinase 3 (FLT3), such as internal tandem duplications (ITDs), can be found in up to 23% of patients with acute myeloid leukemia (AML) and confer a poor prognosis. Current treatment options for FLT3(ITD)-positive AMLs include genotoxic therapy and FLT3 inhibitors (FLT3i’s), which are rarely curative. PARP1 inhibitors (PARP1i’s) have been successfully applied to induce synthetic lethality in tumors harboring BRCA1/2 mutations and displaying homologous recombination (HR) deficiency. We show here that inhibition of FLT3(ITD) activity by the FLT3i AC220 caused downregulation of DNA repair proteins BRCA1, BRCA2, PALB2, RAD51, and LIG4, resulting in inhibition of 2 major DNA double-strand break (DSB) repair pathways, HR, and nonhomologous end-joining. PARP1i, olaparib, and BMN673 caused accumulation of lethal DSBs and cell death in AC220-treated FLT3(ITD)-positive leukemia cells, thus mimicking synthetic lethality. Moreover, the combination of FLT3i and PARP1i eliminated FLT3(ITD)-positive quiescent and proliferating leukemia stem cells, as well as leukemic progenitors, from human and mouse leukemia samples. Notably, the combination of AC220 and BMN673 significantly delayed disease onset and effectively reduced leukemia-initiating cells in an FLT3(ITD)-positive primary AML xenograft mouse model. In conclusion, we postulate that FLT3i-induced deficiencies in DSB repair pathways sensitize FLT3(ITD)-positive AML cells to synthetic lethality triggered by PARP1i’s. Therefore, FLT3(ITD) could be used as a precision medicine marker for identifying AML patients that may benefit from a therapeutic regimen combining FLT3 and PARP1i’s.
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- 2018
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36. BCL11B, the Cerberus of human leukemia.
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Meijerink JPP
- Subjects
- Humans, Transcription Factors, Tumor Suppressor Proteins, Leukemia genetics, Repressor Proteins
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- 2021
- Full Text
- View/download PDF
37. PAX5 is a tumor suppressor in mouse mutagenesis models of acute lymphoblastic leukemia
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Charles G. Mullighan, Chunxu Qu, Xiaoping Su, Lei Wei, Debbie Payne-Turner, Jinghui Zhang, Alistair G. Rust, James R. Downing, Jing Ma, David J. Adams, Louise van der Weyden, Kathryn G. Roberts, Jeroen de Ridder, Jinjun Dang, Laura J. Janke, Robert Huether, Brenda A. Schulman, Jinjun Cheng, Guangchun Song, and Gang Wu
- Subjects
Immunology ,Biology ,Biochemistry ,law.invention ,Mice ,immune system diseases ,law ,Transcription (biology) ,hemic and lymphatic diseases ,medicine ,Animals ,Transcription factor ,Gene ,Lymphoid Neoplasia ,Activator (genetics) ,Tumor Suppressor Proteins ,PAX5 Transcription Factor ,Neoplasms, Experimental ,Cell Biology ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Mice, Mutant Strains ,Leukemia ,Cancer research ,Suppressor ,PAX5 ,Haploinsufficiency ,Gene Deletion - Abstract
Alterations of genes encoding transcriptional regulators of lymphoid development are a hallmark of B-progenitor acute lymphoblastic leukemia (B-ALL) and most commonly involve PAX5, encoding the DNA-binding transcription factor paired-box 5. The majority of PAX5 alterations in ALL are heterozygous, and key PAX5 target genes are expressed in leukemic cells, suggesting that PAX5 may be a haploinsufficient tumor suppressor. To examine the role of PAX5 alterations in leukemogenesis, we performed mutagenesis screens of mice heterozygous for a loss-of-function Pax5 allele. Both chemical and retroviral mutagenesis resulted in a significantly increased penetrance and reduced latency of leukemia, with a shift to B-lymphoid lineage. Genomic profiling identified a high frequency of secondary genomic mutations, deletions, and retroviral insertions targeting B-lymphoid development, including Pax5, and additional genes and pathways mutated in ALL, including tumor suppressors, Ras, and Janus kinase-signal transducer and activator of transcription signaling. These results show that in contrast to simple Pax5 haploinsufficiency, multiple sequential alterations targeting lymphoid development are central to leukemogenesis and contribute to the arrest in lymphoid maturation characteristic of ALL. This cross-species analysis also validates the importance of concomitant alterations of multiple cellular growth, signaling, and tumor suppression pathways in the pathogenesis of B-ALL.
- Published
- 2015
38. FLT3-ITD and TLR9 use Bruton tyrosine kinase to activate distinct transcriptional programs mediating AML cell survival and proliferation
- Author
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Carmen Döbele, Thomas Oellerich, Christina Perske, Julia Beck, Hubert Serve, Jasmin Corso, Gesine Bug, Henning Urlaub, Hanibal Bohnenberger, Sebastian Mohr, Anjali Cremer, Helene Braun, Silvia Münch, Johannes Wicht, Mark F. Oellerich, and Ekkehard Schütz
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Adult ,Myeloid ,Cell Survival ,Immunology ,Apoptosis ,Bone Marrow Cells ,Context (language use) ,Biochemistry ,Mass Spectrometry ,Young Adult ,immune system diseases ,Cell Line, Tumor ,hemic and lymphatic diseases ,Agammaglobulinaemia Tyrosine Kinase ,STAT5 Transcription Factor ,medicine ,Humans ,Bruton's tyrosine kinase ,Phosphorylation ,Cell Proliferation ,biology ,Gene Expression Regulation, Leukemic ,Tumor Suppressor Proteins ,Cell Cycle ,NF-kappa B ,Myeloid leukemia ,Cell Biology ,Hematology ,Middle Aged ,Protein-Tyrosine Kinases ,Cell cycle ,medicine.disease ,Immunohistochemistry ,Enzyme Activation ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,fms-Like Tyrosine Kinase 3 ,Toll-Like Receptor 9 ,biology.protein ,Cancer research ,Tyrosine ,Signal transduction ,Signal Transduction - Abstract
Acute myeloid leukemia (AML) is driven by niche-derived and cell-autonomous stimuli. Although many cell-autonomous disease drivers are known, niche-dependent signaling in the context of the genetic disease heterogeneity has been difficult to investigate. Here, we analyzed the role of Bruton tyrosine kinase (BTK) in AML. BTK was frequently expressed, and its inhibition strongly impaired the proliferation and survival of AML cells also in the presence of bone marrow stroma. By interactome analysis, (phospho)proteomics, and transcriptome sequencing, we characterized BTK signaling networks. We show that BTK-dependent signaling is highly context dependent. In Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)–positive AML, BTK mediates FLT3-ITD–dependent Myc and STAT5 activation, and combined targeting of FLT3-ITD and BTK showed additive effects. In Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)–negative AML, BTK couples Toll-like receptor 9 (TLR9) activation to nuclear factor κΒ and STAT5. Both BTK-dependent transcriptional programs were relevant for cell cycle progression and apoptosis regulation. Thus, we identify context-dependent oncogenic driver events that may guide subtype-specific treatment strategies and, for the first time, point to a role of TLR9 in AML. Clinical evaluation of BTK inhibitors in AML seems warranted.
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- 2015
39. Receptor-type tyrosine-protein phosphatase κ directly targets STAT3 activation for tumor suppression in nasal NK/T-cell lymphoma
- Author
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Tianhuan Guo, Weiping Liu, Yun Wen Chen, Yuen Piu Chan, Eric Tse, Lijun Shen, Rex Au-Yeung, Yok-Lam Kwong, Gopesh Srivastava, KY Wong, Florence Loong, Johnny Cheuk On Tang, William W.L. Choi, Michelle L.Y. Wong, Gan Di Li, Norio Shimizu, and Qian Tao
- Subjects
Male ,STAT3 Transcription Factor ,DNA Mutational Analysis ,Nose Neoplasms ,Immunology ,Phosphatase ,Down-Regulation ,Apoptosis ,Protein tyrosine phosphatase ,Biochemistry ,Cell Line, Tumor ,Humans ,Neoplasm Invasiveness ,RNA, Messenger ,RNA, Neoplasm ,Phosphorylation ,Promoter Regions, Genetic ,STAT3 ,Cell Proliferation ,Cell Nucleus ,biology ,Cell growth ,Tumor Suppressor Proteins ,Receptor-Like Protein Tyrosine Phosphatases, Class 2 ,Cell Biology ,Hematology ,DNA Methylation ,Middle Aged ,Prognosis ,Natural killer T cell ,Molecular biology ,Lymphoma, Extranodal NK-T-Cell ,Caspases ,Gene Knockdown Techniques ,DNA methylation ,Cancer research ,STAT protein ,biology.protein ,Female ,Gene Deletion ,Protein Binding - Abstract
Nasal-type natural killer/T-cell lymphoma (NKTCL) is an aggressive disease characterized by frequent deletions on 6q, and constitutive activation of signal transducer and activator of transcription 3 (STAT3). Phosphorylation at Tyr705 activates STAT3, inducing dimerization, nuclear translocation, and DNA binding. In this study, we investigated whether receptor-type tyrosine-protein phosphatase κ (PTPRK), the only protein tyrosine phosphatase at 6q that contains a STAT3-specifying motif, negatively regulates STAT3 activation in NKTCL. PTPRK was highly expressed in normal NK cells but was underexpressed in 4 of 5 (80%) NKTCL cell lines and 15 of 27 (55.6%) primary tumors. Significantly, PTPRK protein expression was inversely correlated with nuclear phospho-STAT3(Tyr705) expression in NKTCL cell lines (P = .025) and tumors (P = .040). PTPRK restoration decreased nuclear phospho-STAT3(Tyr705) levels, whereas knockdown of PTPRK increased such levels in NKTCL cells. Phosphatase substrate-trapping mutant assays demonstrated the binding of PTPRK to STAT3, and phosphatase assays showed that PTPRK directly dephosphorylated phospho-STAT3(Tyr705). Restoration of PTPRK inhibited tumor cell growth and reduced the migration and invasion ability of NKTCL cells. Monoallelic deletion and promoter hypermethylation caused underexpression of PTPRK messenger RNA in NKTCL, and methylation of the PTPRK promoter significantly correlated with inferior overall survival (P = .049) in NKTCL patients treated with the steroid-dexamethasone, methotrexate, ifosfamide, l-asparaginase, and etoposide regimen. Altogether, our findings show that PTPRK underexpression leads to STAT3 activation and contributes to NKTCL pathogenesis.
- Published
- 2015
40. Loss of PRDM11 promotes MYC-driven lymphomagenesis
- Author
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Carsten Friis, Kirsten Grønbæk, Linda Jacobsen, Christophe Côme, Klaus T. Jensen, Louise Rosgaard, Anders H. Lund, Cathrine K. Fog, Alison Louw, Fazila Asmar, Arie Koen Braat, Jens Vilstrup Johansen, Maarten van Lohuizen, Kristian Anthonsen, Elisabeth Ralfkiaer, Nina Friesgaard Øbro, Hanne Vibeke Marquart, and Tony Bou Kheir
- Subjects
Lymphoma ,Molecular Sequence Data ,Immunology ,Biology ,Biochemistry ,law.invention ,Proto-Oncogene Proteins c-myc ,Gene Knockout Techniques ,Mice ,law ,medicine ,Animals ,Humans ,Gene ,Transcription factor ,Cells, Cultured ,Regulation of gene expression ,Tumor Suppressor Proteins ,HEK 293 cells ,Cell Biology ,Hematology ,Embryo, Mammalian ,medicine.disease ,Molecular biology ,Gene Expression Regulation, Neoplastic ,Cell Transformation, Neoplastic ,HEK293 Cells ,Knockout mouse ,Cancer research ,Suppressor ,Lymphoma, Large B-Cell, Diffuse ,Carrier Proteins ,Diffuse large B-cell lymphoma ,Gene Deletion ,HeLa Cells ,Transcription Factors - Abstract
The PR-domain (PRDM) family of genes encodes transcriptional regulators, several of which are deregulated in cancer. By using a functional screening approach, we sought to identify novel tumor suppressors among the PRDMs. Here we demonstrate oncogenic collaboration between depletion of the previously uncharacterized PR-domain family member Prdm11 and overexpression of MYC. Overexpression of PRDM11 inhibits proliferation and induces apoptosis. Prdm11 knockout mice are viable, and loss of Prdm11 accelerates MYC-driven lymphomagenesis in the Eµ-Myc mouse model. Moreover, we show that patients with PRDM11-deficient diffuse large B-cell lymphomas (DLBCLs) have poorer overall survival and belong to the nongerminal center B-cell-like subtype. Mechanistically, genome-wide mapping of PRDM11 binding sites coupled with transcriptome sequencing in human DLBCL cells evidenced that PRDM11 associates with transcriptional start sites of target genes and regulates important oncogenes such as FOS and JUN. Hence, we characterize PRDM11 as a putative novel tumor suppressor that controls the expression of key oncogenes, and we add new mechanistic insight into B-cell lymphomagenesis.
- Published
- 2015
41. HIF-1α can act as a tumor suppressor gene in murine acute myeloid leukemia
- Author
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David Bryder, Axel Hyrenius-Wittsten, Matilda Rehn, Talia Velasco-Hernandez, and Jörg Cammenga
- Subjects
Myeloid ,Immunology ,Mice, Transgenic ,Biology ,Biochemistry ,Mice ,hemic and lymphatic diseases ,medicine ,Animals ,Genes, Tumor Suppressor ,Cellular localization ,Tumor Suppressor Proteins ,Myeloid leukemia ,Neoplasms, Experimental ,Cell Biology ,Hematology ,Hematopoietic Stem Cells ,Hypoxia-Inducible Factor 1, alpha Subunit ,medicine.disease ,Leukemia, Myeloid, Acute ,Haematopoiesis ,Leukemia ,medicine.anatomical_structure ,Hypoxia-inducible factors ,Bone marrow ,Stem cell ,Gene Deletion - Abstract
Self-renewal of hematopoietic stem cells (HSCs) and leukemia-initiating cells (LICs) has been proposed to be influenced by low oxygen tension (hypoxia). This signaling, related to the cellular localization inside the bone marrow niche and/or influenced by extrinsic factors, promotes the stabilization of hypoxia inducible factors (HIFs). Whether HIF-1α can be used as a therapeutic target in the treatment of myeloid malignancies remains unknown. We have used three different murine models to investigate the role of HIF-1α in acute myeloid leukemia (AML) initiation/progression and self-renewal of LICs. Unexpectedly, we failed to observe a delay or prevention of disease development from hematopoietic cells lacking Hif-1α. In contrast, deletion of Hif-1α resulted in faster development of the disease and an enhanced leukemia phenotype in some of the investigated models. Our results therefore warrant a reconsideration of the role of HIF-1α and, as a consequence, question its generic therapeutic usefulness in AML.
- Published
- 2014
42. Modeling de novo leukemogenesis from human cord blood with MN1 and NUP98HOXD13
- Author
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Gyeongsin Park, Michael Heuser, Connie J. Eaves, Andrew P. Weng, Garrett W. Rhyasen, Maura Gasparetto, Suzan Imren, Yeonsook Moon, Philip A. Beer, Tobias Berg, Ling Chen, Gudmundur L. Norddahl, Ping Xiang, Patricia Rosten, and R. Keith Humphries
- Subjects
Myeloid ,Stromal cell ,Oncogene Proteins, Fusion ,Immunology ,Mice, Transgenic ,Mice, SCID ,Biology ,Biochemistry ,Mice, Inbred NOD ,Genetic model ,Myeloproliferation ,medicine ,Animals ,Humans ,Myeloid Neoplasia ,Tumor Suppressor Proteins ,Myeloid leukemia ,Neoplasms, Experimental ,Cell Biology ,Hematology ,Fetal Blood ,medicine.disease ,Leukemia, Myeloid, Acute ,Leukemia ,Cell Transformation, Neoplastic ,medicine.anatomical_structure ,Cord blood ,Trans-Activators ,Cancer research ,Stem cell - Abstract
Leukemic transformation of human cells is a complex process. Here we show that forced expression of MN1 in primitive human cord blood cells maintained on stromal cells in vitro induces a transient, but not serially transplantable, myeloproliferation in engrafted mice. However, cotransduction of an activated HOX gene (NUP98HOXD13) with MN1 induces a serially transplantable acute myeloid leukemia (AML). Further characterization of the leukemic cells generated from the dually transduced cells showed the activation of stem cell gene expression signatures also found in primary human AML. These findings show a new forward genetic model of human leukemogenesis and further highlight the relevance of homeobox transcription factors in the transformation process.
- Published
- 2014
43. "Root"ing for successful T-ALL treatment.
- Author
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Padi SKR and Kraft AS
- Subjects
- Humans, Tumor Suppressor Proteins, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
- Published
- 2021
- Full Text
- View/download PDF
44. CUX1 in leukemia: dosage matters.
- Author
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Boultwood, Jacqueline
- Subjects
- *
TUMOR suppressor proteins , *ACUTE myeloid leukemia , *HUMAN chromosomes , *GENE expression , *CANCER invasiveness - Abstract
The article discusses a study on the classification of homeodomain protein CUX1 as a tumor suppressor gene (TSG) that shows recurrent inactivation in acute myeloid leukemia (AML). It notes that the complete loss of chromosome 7 and partial deletion of the long arm of chromosome 7 are chronic abnormalities in malignant myeloid disorders. The data gathered in the study also reveals that elevated CUX1 expression has an important role in tumor progression.
- Published
- 2013
- Full Text
- View/download PDF
45. ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes
- Author
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Alina Nicolae, Stephen M. Ansell, Sarah L. Ondrejka, Jonathan W. Said, Shridevi Karikehalli, Karen L. Grogg, Ahmet Dogan, Edgardo R. Parrilla Castellar, Wyndham H. Wilson, Andrew L. Feldman, Rhett P. Ketterling, Elaine S. Jaffe, William R. Macon, Sarah E. Gibson, Eric D. Hsi, Jagmohan S. Sidhu, Mark E. Law, Steven H. Swerdlow, Liuyan Jiang, James R. Cerhan, Cristine Allmer, Matthew J. Maurer, Kay M. Ristow, Ryan A. Knudson, George Vasmatzis, and Thomas M. Habermann
- Subjects
Adult ,Male ,Adolescent ,Immunology ,Kaplan-Meier Estimate ,Biology ,Biochemistry ,Young Adult ,International Prognostic Index ,Inside BLOOD Commentary ,hemic and lymphatic diseases ,Biomarkers, Tumor ,medicine ,Humans ,Anaplastic lymphoma kinase ,Anaplastic Lymphoma Kinase ,Child ,Anaplastic large-cell lymphoma ,In Situ Hybridization, Fluorescence ,Aged ,Aged, 80 and over ,Gene Rearrangement ,Genetic heterogeneity ,Tumor Suppressor Proteins ,Large cell ,Receptor Protein-Tyrosine Kinases ,Cell Biology ,Hematology ,Gene rearrangement ,Middle Aged ,Prognosis ,medicine.disease ,Immunohistochemistry ,Lymphoma ,Transplantation ,Interferon Regulatory Factors ,Cancer research ,Dual-Specificity Phosphatases ,Lymphoma, Large-Cell, Anaplastic ,Mitogen-Activated Protein Kinase Phosphatases ,Female ,Transcription Factors - Abstract
Anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a CD30-positive T-cell non-Hodgkin lymphoma that morphologically resembles ALK-positive ALCL but lacks chromosomal rearrangements of the ALK gene. The genetic and clinical heterogeneity of ALK-negative ALCL has not been delineated. We performed immunohistochemistry and fluorescence in situ hybridization on 73 ALK-negative ALCLs and 32 ALK-positive ALCLs and evaluated the associations among pathology, genetics, and clinical outcome. Chromosomal rearrangements of DUSP22 and TP63 were identified in 30% and 8% of ALK-negative ALCLs, respectively. These rearrangements were mutually exclusive and were absent in ALK-positive ALCLs. Five-year overall survival rates were 85% for ALK-positive ALCLs, 90% for DUSP22-rearranged ALCLs, 17% for TP63-rearranged ALCLs, and 42% for cases lacking all 3 genetic markers (P < .0001). Hazard ratios for death in these 4 groups after adjusting for International Prognostic Index and age were 1.0 (reference group), 0.58, 8.63, and 4.16, respectively (P = 7.10 × 10−5). These results were similar when restricted to patients receiving anthracycline-based chemotherapy, as well as to patients not receiving stem cell transplantation. Thus, ALK-negative ALCL is a genetically heterogeneous disease with widely disparate outcomes following standard therapy. DUSP22 and TP63 rearrangements may serve as predictive biomarkers to help guide patient management.
- Published
- 2014
46. Constitutive activation of STAT5A and STAT5B regulates IgM secretion in Waldenström's macroglobulinemia
- Author
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Frank J. Secreto, Anne J. Novak, Zhi Zhang Yang, Stephen M. Ansell, Steven C. Ziesmer, and Lucy S. Hodge
- Subjects
Transcriptional Activation ,Immunology ,STAT5B ,Biochemistry ,hemic and lymphatic diseases ,STAT5 Transcription Factor ,medicine ,Humans ,RNA, Small Interfering ,Cells, Cultured ,STAT5 ,Secretory Pathway ,biology ,Tumor Suppressor Proteins ,food and beverages ,Waldenstrom macroglobulinemia ,Macroglobulinemia ,Cell Biology ,Hematology ,medicine.disease ,Molecular biology ,LYMPHOID NEOPLASIA ,HEK293 Cells ,Gene Expression Regulation ,Immunoglobulin M ,Gene Knockdown Techniques ,biology.protein ,STAT protein ,Cancer research ,Waldenstrom Macroglobulinemia ,Signal transduction ,Janus Kinase Family - Abstract
Activation of the Janus kinase family/signal transducer and activator of transcription (JAK/STAT) signaling pathway has been associated with the pathogenesis and progression of both solid and hematologic malignancies. We have detected constitutive activation of STAT5 in malignant B cells derived from patients with Waldenström's macroglobulinemia (WM). Although short hairpin RNA-mediated knockdown of the STAT5A and STAT5B isoforms did not affect cellular proliferation, loss of STAT5 significantly decreased immunoglobulin M (IgM) secretion. A similar dose-dependent inhibition of IgM secretion was observed when WM cell lines were treated with a small molecule inhibitor of STAT5. These data suggest that STAT5 is involved in regulating IgM production in WM and that inhibition of STAT5 may represent a novel therapeutic strategy for lowering IgM levels in WM patients.
- Published
- 2014
47. Gain-of-function
- Author
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Josef Davidsson, Yenan T. Bryceson, Samuel C. C. Chiang, Jonna Komulainen-Ebrahim, Johanna Uusimaa, David Bryder, Jörg Cammenga, Riitta Niinimäki, Hannaleena Kokkonen, Merja Möttönen, Andreas Puschmann, Jan-Inge Henter, Elisa Rahikkala, Jukka S. Moilanen, Hong Qian, Tim Ripperger, Bianca Tesi, Tim D. Holmes, Ulf Tedgård, Sorina Gorcenco, Alexandra Rundberg Nilsson, Matthias Voss, Lennart Nilsson, Thoas Fioretos, and Cornelis J.H. Pronk
- Subjects
0301 basic medicine ,Adult ,Male ,Heterozygote ,Myeloid ,Tumor suppressor gene ,Pancytopenia ,Immunology ,Gene Expression ,Biology ,medicine.disease_cause ,Biochemistry ,Immunophenotyping ,03 medical and health sciences ,medicine ,Missense mutation ,Humans ,Cognitive Dysfunction ,Myeloid Cells ,Child ,Immunodeficiency ,Alleles ,Cell Proliferation ,Chromosome 7 (human) ,Cytopenia ,Mutation ,B-Lymphocytes ,Myeloid Neoplasia ,Mosaicism ,Tumor Suppressor Proteins ,Immunologic Deficiency Syndromes ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Uniparental disomy ,Hematopoiesis ,Pedigree ,Killer Cells, Natural ,030104 developmental biology ,medicine.anatomical_structure ,Myelodysplastic Syndromes ,Interferon Type I ,Female ,Chromosomes, Human, Pair 7 - Abstract
Several monogenic causes of familial myelodysplastic syndrome (MDS) have recently been identified. We studied 2 families with cytopenia, predisposition to MDS with chromosome 7 aberrations, immunodeficiency, and progressive cerebellar dysfunction. Genetic studies uncovered heterozygous missense mutations in SAMD9L, a tumor suppressor gene located on chromosome arm 7q. Consistent with a gain-of-function effect, ectopic expression of the 2 identified SAMD9L mutants decreased cell proliferation relative to wild-type protein. Of the 10 individuals identified who were heterozygous for either SAMD9L mutation, 3 developed MDS upon loss of the mutated SAMD9L allele following intracellular infections associated with myeloid, B-, and natural killer (NK)-cell deficiency. Five other individuals, 3 with spontaneously resolved cytopenic episodes in infancy, harbored hematopoietic revertant mosaicism by uniparental disomy of 7q, with loss of the mutated allele or additional in cisSAMD9L truncating mutations. Examination of 1 individual indicated that somatic reversions were postnatally selected. Somatic mutations were tracked to CD34+ hematopoietic progenitor cell populations, being further enriched in B and NK cells. Stimulation of these cell types with interferon (IFN)-α or IFN-γ induced SAMD9L expression. Clinically, revertant mosaicism was associated with milder disease, yet neurological manifestations persisted in 3 individuals. Two carriers also harbored a rare, in trans germ line SAMD9L missense loss-of-function variant, potentially counteracting the SAMD9L mutation. Our results demonstrate that gain-of-function mutations in the tumor suppressor SAMD9L cause cytopenia, immunodeficiency, variable neurological presentation, and predisposition to MDS with -7/del(7q), whereas hematopoietic revertant mosaicism commonly ameliorated clinical manifestations. The findings suggest a role for SAMD9L in regulating IFN-driven, demand-adapted hematopoiesis.
- Published
- 2016
48. A far downstream enhancer for murine Bcl11b controls its T-cell specific expression
- Author
-
Marei Dose, Hao Yuan Kueh, Long Li, Ellen V. Rothenberg, Fotini Gounari, Ruzbeh Mosadeghi, and Jingli A. Zhang
- Subjects
Hematopoiesis and Stem Cells ,T-Lymphocytes ,Immunology ,Repressor ,Biology ,Proto-Oncogene Mas ,Biochemistry ,Histones ,Mice ,Genes, Reporter ,Animals ,Gene silencing ,Cell Lineage ,Gene Silencing ,Promoter Regions, Genetic ,Downstream Enhancer ,Gene ,Transcription factor ,Regulation of gene expression ,Tumor Suppressor Proteins ,Cell Biology ,Hematology ,DNA Methylation ,Hematopoietic Stem Cells ,Molecular biology ,Repressor Proteins ,Enhancer Elements, Genetic ,Gene Expression Regulation ,CpG site ,DNA methylation ,CpG Islands ,Transcription Factors - Abstract
Bcl11b is a T-cell specific gene in hematopoiesis that begins expression during T-lineage commitment and is required for this process. Aberrant expression of BCL11B or proto-oncogene translocation to the vicinity of BCL11B can be a contributing factor in human T-ALL. To identify the mechanism that controls its distinctive T-lineage expression, we corrected the identified Bcl11b transcription start site and mapped a cell-type-specific differentially methylated region bracketing the Bcl11b promoter. We identified a 1.9-kb region 850 kb downstream of Bcl11b, "Major Peak," distinguished by its dynamic histone marking pattern in development that mirrors the pattern at the Bcl11b promoter. Looping interactions between promoter-proximal elements including the differentially methylated region and downstream elements in the Major Peak are required to recapitulate the T-cell specific expression of Bcl11b in stable reporter assays. Functional dissection of the Major Peak sequence showed distinct subregions, in which TCF-1 sites and a conserved element were required for T-lineage-specific activation and silencing in non-T cells. A bacterial artificial chromosome encompassing the full Bcl11b gene still required the addition of the Major Peak to exhibit T-cell specific expression. Thus, promoter-proximal and Major Peak sequences are cis-regulatory elements that interact over 850 kb to control expression of Bcl11b in hematopoietic cells.
- Published
- 2013
49. Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia
- Author
-
Pekka Ellonen, Thomas L. Olson, Thomas P. Loughran, Olli Kallioniemi, Hanna Rajala, Caroline A. Heckman, Satu Mustjoki, Samuli Eldfors, Andy Awwad, Emma I. Andersson, Sonja Lagström, Michael J. Clemente, Arjan J. van Adrichem, Kimmo Porkka, Heikki Kuusanmäki, Yiyi Yan, Jaroslaw P. Maciejewski, Dan Zhang, Andres Jerez, and Krister Wennerberg
- Subjects
Male ,animal structures ,Transcription, Genetic ,Somatic cell ,Large granular lymphocytic leukemia ,Immunology ,STAT5B ,chemical and pharmacologic phenomena ,Biology ,Biochemistry ,Cohort Studies ,src Homology Domains ,03 medical and health sciences ,0302 clinical medicine ,STAT5 Transcription Factor ,medicine ,Humans ,Cytotoxic T cell ,Missense mutation ,Exome ,Genetic Testing ,Phosphorylation ,STAT5 ,Aged ,030304 developmental biology ,0303 health sciences ,Lymphoid Neoplasia ,Tumor Suppressor Proteins ,food and beverages ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Molecular biology ,Protein Structure, Tertiary ,3. Good health ,Leukemia, Large Granular Lymphocytic ,Leukemia ,Mutagenesis ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,biology.protein ,Female ,Dimerization ,hormones, hormone substitutes, and hormone antagonists ,HeLa Cells - Abstract
Large granular lymphocytic (LGL) leukemia is characterized by clonal expansion of cytotoxic T cells or natural killer cells. Recently, somatic mutations in the signal transducer and activator of transcription 3 (STAT3) gene were discovered in 28% to 40% of LGL leukemia patients. By exome and transcriptome sequencing of 2 STAT3 mutation-negative LGL leukemia patients, we identified a recurrent, somatic missense mutation (Y665F) in the Src-like homology 2 domain of the STAT5b gene. Targeted amplicon sequencing of 211 LGL leukemia patients revealed 2 additional patients with STAT5b mutations (N642H), resulting in a total frequency of 2% (4 of 211) of STAT5b mutations across all patients. The Y665F and N642H mutant constructs increased the transcriptional activity of STAT5 and tyrosine (Y694) phosphorylation, which was also observed in patient samples. The clinical course of the disease in patients with the N642H mutation was aggressive and fatal, clearly different from typical LGL leukemia with a relatively favorable outcome. This is the first time somatic STAT5 mutations are discovered in human cancer and further emphasizes the role of STAT family genes in the pathogenesis of LGL leukemia.
- Published
- 2013
50. The E3 ubiquitin ligase UBR5 is recurrently mutated in mantle cell lymphoma
- Author
-
Sanja Rogic, Marco A. Marra, Richard A. Moore, Christian Steidl, Raymond S. Lim, Kane Tse, David W. Scott, Randy D. Gascoyne, Andrew J. Mungall, Joseph M. Connors, Robert Kridel, and Barbara Meissner
- Subjects
Nonsynonymous substitution ,Ubiquitin-Protein Ligases ,Molecular Sequence Data ,Immunology ,Cell Cycle Proteins ,Ataxia Telangiectasia Mutated Proteins ,Lymphoma, Mantle-Cell ,Protein Serine-Threonine Kinases ,medicine.disease_cause ,Biochemistry ,Cohort Studies ,Exon ,Cyclin D1 ,Cell Line, Tumor ,hemic and lymphatic diseases ,medicine ,Humans ,Amino Acid Sequence ,Receptor, Notch1 ,Gene ,Sequence Deletion ,Genetics ,Mutation ,Base Sequence ,biology ,Tumor Suppressor Proteins ,Cell Biology ,Hematology ,medicine.disease ,Molecular biology ,Ubiquitin ligase ,DNA-Binding Proteins ,biology.protein ,Mantle cell lymphoma ,Tumor Suppressor Protein p53 ,Sequence Alignment - Abstract
We have recently reported the application of RNAseq to mantle cell lymphoma (MCL) transcriptomes revealing recurrent mutations in NOTCH1. Here we describe the targeted resequencing of 18 genes mutated in this discovery cohort using a larger cohort of MCL tumors. In addition to frequent mutations in ATM, CCND1, TP53, and NOTCH1, mutations were also observed recurrently in MEF2B, TRAF2, and TET2. Interestingly, the third most frequently mutated gene was UBR5, a gene encoding a 2799aa protein, with multiple functions, including E3 ligase activity based on a conserved cysteine residue at the C-terminus. Nonsynonymous mutations were detected in 18% (18/102) of tumors, with 61% of the mutations resulting in frameshifts in, or around, exon 58, predicted to result in the loss of this conserved cysteine residue. The recurrence and clustering of deleterious mutations implicate UBR5 mutations as a critical pathogenic event in a subgroup of MCL.
- Published
- 2013
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