28 results on '"Hurtz C"'
Search Results
2. Pre-BCR signaling in precursor B-cell acute lymphoblastic leukemia regulates PI3K/AKT, FOXO1 and MYC, and can be targeted by SYK inhibition
- Author
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Köhrer, S, Havranek, O, Seyfried, F, Hurtz, C, Coffey, G P, Kim, E, ten Hacken, E, Jäger, U, Vanura, K, O'Brien, S, Thomas, D A, Kantarjian, H, Ghosh, D, Wang, Z, Zhang, M, Ma, W, Jumaa, H, Debatin, K-M, Müschen, M, Meyer, L H, Davis, R E, and Burger, J A
- Published
- 2016
- Full Text
- View/download PDF
3. Metabolic gatekeeper function of B-lymphoid transcription factors (vol 542, pg 479, 2017)
- Author
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Chan, LN, Chen, Z, Braas, D, Lee, J-W, Xiao, G, Geng, H, Cosgun, KN, Hurtz, C, Shojaee, S, Cazzaniga, V, Schjerven, H, Ernst, T, Hochhaus, A, Kornblau, SM, Konopleva, M, Pufall, MA, Cazzaniga, G, Liu, GJ, Milne, TA, Koeffler, HP, Ross, TS, Sanchez-Garcia, I, Borkhardt, A, Yamamoto, KR, Dickins, RA, Graeber, TG, and Muschen, M
- Abstract
In Fig. 3c of this Letter, the the effects of CRISPR-Cas9-mediated deletion of NR3C1, TXNIP and CNR2 in patient-derived B-lineage leukaemia cells were shown. For curves depicting NR3C1 (left graph), data s for TXNIP (middle graph) were inadvertently plotted. This figure has been corrected online, and the original Fig. 3c is shown as Supplementary Information to this Amendment for transparency. The error does not affect the conclusions of the Letter. In addition, Source Data files have been added for the Figs. 1-4 and Extended Data Figs. 1-10 of the original Letter.
- Published
- 2018
4. Adaptation of the Brazilian version of the Utrecht Work Engagement Scale
- Author
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Souza Vasquez, A, Dos Santos, E, Paico, E, Hurtz, C, Schaufeli, W.B., Leerstoel Schaufeli, and Work and Organizational Psychology: Occupational Health Psychology
- Subjects
Positive Psychology ,Work engagement ,test validation ,psychological assessment - Abstract
Engagement at work is a positive mental and dispositional state characterized by Vigor, Dedication and Concentration. The aim of this study was to adapt and get evidence of validity for the Brazilian version of the utrecht work engagement scale (UWES). Participated in the study 1167 workers between 18 and 70 years (M = 36.8, SD = 10.3) in the Brazilian regions. Studies to establish content and construct validity with the 17- item and the 9- item scales were performed. Exploratory and confirmatory factor analyzes showed that the best solution is unifactorial. Internal consistency was high. Age differences in engagement were found. The results also indicate that the present version of UWES is valid for use in Brazil and reinforce the idea that engagement at work is a universal construct. Although most of the results agree with the findings reported in the literature, some cultural differences appeared and they are discussed in this paper.
- Published
- 2015
5. P324: PHARMACOLOGIC INHIBITION OF DYRK1A RENDERS HIGH‐RISK KMT2A‐R ALL SENSITIVE TO VENETOCLAX.
- Author
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Hurtz, C., Wertheim, G., Chukinas, J., Bhansali, R., Swaminathan, S., Crispino, J., Shi, J., Tasian, S., and Carroll, M.
- Published
- 2022
- Full Text
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6. 4'-Ethynyl-2'-Deoxycytidine (EdC) Preferentially Targets Lymphoma and Leukemia Subtypes by Inducing Replicative Stress.
- Author
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Calbert ML, Chandramouly G, Adams CM, Saez-Ayala M, Kent T, Tyagi M, Ayyadevara VSSA, Wang Y, Krais JJ, Gordon J, Atkins J, Toma MM, Betzi S, Boghossian AS, Rees MG, Ronan MM, Roth JA, Goldman AR, Gorman N, Mitra R, Childers WE, Graña X, Skorski T, Johnson N, Hurtz C, Morelli X, Eischen CM, and Pomerantz RT
- Subjects
- Humans, Animals, Mice, Cell Line, Tumor, Lymphoma drug therapy, Lymphoma pathology, Lymphoma metabolism, Xenograft Model Antitumor Assays, Leukemia drug therapy, Leukemia pathology, Deoxycytidine Kinase metabolism, Deoxycytidine analogs & derivatives, Deoxycytidine pharmacology
- Abstract
Anticancer nucleosides are effective against solid tumors and hematologic malignancies, but typically are prone to nucleoside metabolism resistance mechanisms. Using a nucleoside-specific multiplexed high-throughput screening approach, we discovered 4'-ethynyl-2'-deoxycytidine (EdC) as a third-generation anticancer nucleoside prodrug with preferential activity against diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL). EdC requires deoxycytidine kinase (DCK) phosphorylation for its activity and induces replication fork arrest and accumulation of cells in S-phase, indicating it acts as a chain terminator. A 2.1Å cocrystal structure of DCK bound to EdC and UDP reveals how the rigid 4'-alkyne of EdC fits within the active site of DCK. Remarkably, EdC was resistant to cytidine deamination and SAMHD1 metabolism mechanisms and exhibited higher potency against ALL compared with FDA-approved nelarabine. Finally, EdC was highly effective against DLBCL tumors and B-ALL in vivo. These data characterize EdC as a preclinical nucleoside prodrug candidate for DLBCL and ALL., (©2023 American Association for Cancer Research.)
- Published
- 2024
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7. Synergistic roles of DYRK1A and GATA1 in trisomy 21 megakaryopoiesis.
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Sit YT, Takasaki K, An HH, Xiao Y, Hurtz C, Gearhart PA, Zhang Z, Gadue P, French DL, and Chou ST
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- Humans, GATA1 Transcription Factor genetics, Thrombopoiesis genetics, Down Syndrome genetics, Down Syndrome complications, Leukemia, Megakaryoblastic, Acute complications, Leukemia, Megakaryoblastic, Acute genetics
- Abstract
Patients with Down syndrome (DS), or trisomy 21 (T21), are at increased risk of transient abnormal myelopoiesis (TAM) and acute megakaryoblastic leukemia (ML-DS). Both TAM and ML-DS require prenatal somatic mutations in GATA1, resulting in the truncated isoform GATA1s. The mechanism by which individual chromosome 21 (HSA21) genes synergize with GATA1s for leukemic transformation is challenging to study, in part due to limited human cell models with wild-type GATA1 (wtGATA1) or GATA1s. HSA21-encoded DYRK1A is overexpressed in ML-DS and may be a therapeutic target. To determine how DYRK1A influences hematopoiesis in concert with GATA1s, we used gene editing to disrupt all 3 alleles of DYRK1A in isogenic T21 induced pluripotent stem cells (iPSCs) with and without the GATA1s mutation. Unexpectedly, hematopoietic differentiation revealed that DYRK1A loss combined with GATA1s leads to increased megakaryocyte proliferation and decreased maturation. This proliferative phenotype was associated with upregulation of D-type cyclins and hyperphosphorylation of Rb to allow E2F release and derepression of its downstream targets. Notably, DYRK1A loss had no effect in T21 iPSCs or megakaryocytes with wtGATA1. These surprising results suggest that DYRK1A and GATA1 may synergistically restrain megakaryocyte proliferation in T21 and that DYRK1A inhibition may not be a therapeutic option for GATA1s-associated leukemias.
- Published
- 2023
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8. B-cell lymphoblastic leukemia in an adolescent with Dravet syndrome.
- Author
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Alzobi M, Hurtz C, Mehta H, Thomas S, and Corey SJ
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- Humans, Adolescent, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, Lymphocytic, Chronic, B-Cell, Epilepsies, Myoclonic
- Published
- 2023
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9. Intrinsic suppression of type I interferon production underlies the therapeutic efficacy of IL-15-producing natural killer cells in B-cell acute lymphoblastic leukemia.
- Author
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Kumar A, Taghi Khani A, Duault C, Aramburo S, Sanchez Ortiz A, Lee SJ, Chan A, McDonald T, Huang M, Lacayo NJ, Sakamoto KM, Yu J, Hurtz C, Carroll M, Tasian SK, Ghoda L, Marcucci G, Gu Z, Rosen ST, Armenian S, Izraeli S, Chen CW, Caligiuri MA, Forman SJ, Maecker HT, and Swaminathan S
- Subjects
- Humans, Mice, Animals, Interferon-gamma metabolism, Interleukin-15 metabolism, Killer Cells, Natural, Mice, Transgenic, Tumor Microenvironment, Burkitt Lymphoma pathology, Interferon Type I metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology
- Abstract
Background: Type I interferons (IFN-Is), secreted by hematopoietic cells, drive immune surveillance of solid tumors. However, the mechanisms of suppression of IFN-I-driven immune responses in hematopoietic malignancies including B-cell acute lymphoblastic leukemia (B-ALL) are unknown., Methods: Using high-dimensional cytometry, we delineate the defects in IFN-I production and IFN-I-driven immune responses in high-grade primary human and mouse B-ALLs. We develop natural killer (NK) cells as therapies to counter the intrinsic suppression of IFN-I production in B-ALL., Results: We find that high expression of IFN-I signaling genes predicts favorable clinical outcome in patients with B-ALL, underscoring the importance of the IFN-I pathway in this malignancy. We show that human and mouse B-ALL microenvironments harbor an intrinsic defect in paracrine (plasmacytoid dendritic cell) and/or autocrine (B-cell) IFN-I production and IFN-I-driven immune responses. Reduced IFN-I production is sufficient for suppressing the immune system and promoting leukemia development in mice prone to MYC-driven B-ALL. Among anti-leukemia immune subsets, suppression of IFN-I production most markedly lowers the transcription of IL-15 and reduces NK-cell number and effector maturation in B-ALL microenvironments. Adoptive transfer of healthy NK cells significantly prolongs survival of overt ALL-bearing transgenic mice. Administration of IFN-Is to B-ALL-prone mice reduces leukemia progression and increases the frequencies of total NK and NK-cell effectors in circulation. Ex vivo treatment of malignant and non-malignant immune cells in primary mouse B-ALL microenvironments with IFN-Is fully restores proximal IFN-I signaling and partially restores IL-15 production. In B-ALL patients, the suppression of IL-15 is the most severe in difficult-to-treat subtypes with MYC overexpression. MYC overexpression promotes sensitivity of B-ALL to NK cell-mediated killing. To counter the suppressed IFN-I-induced IL-15 production in MYC
high human B-ALL, we CRISPRa-engineered a novel human NK-cell line that secretes IL-15. CRISPRa IL-15-secreting human NK cells kill high-grade human B-ALL in vitro and block leukemia progression in vivo more effectively than NK cells that do not produce IL-15., Conclusion: We find that restoration of the intrinsically suppressed IFN-I production in B-ALL underlies the therapeutic efficacy of IL-15-producing NK cells and that such NK cells represent an attractive therapeutic solution for the problem of drugging MYC in high-grade B-ALL., Competing Interests: Competing interests: The work described in this study is covered by pending US and PCT patent applications assigned to City of Hope and/or Stanford University with inventors SS, AK, ATK, CW-C, SJL, CD and HTM. MAC and JY are cofounders of CytoImmune Therapeutics., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2023
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10. Activated natural killer cells predict poor clinical prognosis in high-risk B- and T-cell acute lymphoblastic leukemia.
- Author
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Duault C, Kumar A, Taghi Khani A, Lee SJ, Yang L, Huang M, Hurtz C, Manning B, Ghoda L, McDonald T, Lacayo NJ, Sakamoto KM, Carroll M, Tasian SK, Marcucci G, Yu J, Caligiuri MA, Maecker HT, and Swaminathan S
- Subjects
- Antigens, CD immunology, Antigens, Differentiation, T-Lymphocyte immunology, CD56 Antigen immunology, Cells, Cultured, Cytokines immunology, Cytotoxicity, Immunologic, Humans, Lectins, C-Type immunology, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Prognosis, Killer Cells, Natural immunology, Lymphocyte Activation, Precursor Cell Lymphoblastic Leukemia-Lymphoma immunology
- Abstract
B- and T-cell acute lymphoblastic leukemia (B/T-ALL) may be refractory or recur after therapy by suppressing host anticancer immune surveillance mediated specifically by natural killer (NK) cells. We delineated the phenotypic and functional defects in NK cells from high-risk patients with B/T-ALL using mass cytometry, flow cytometry, and in silico cytometry, with the goal of further elucidating the role of NK cells in sustaining acute lymphoblastic leukemia (ALL) regression. We found that, compared with their normal counterparts, NK cells from patients with B/T-ALL are less cytotoxic but exhibit an activated signature that is characterized by high CD56, high CD69, production of activated NK cell-origin cytokines, and calcium (Ca2+) signaling. We demonstrated that defective maturation of NK cells into cytotoxic effectors prevents NK cells from ALL from lysing NK cell-sensitive targets as efficiently as do normal NK cells. Additionally, we showed that NK cells in ALL are exhausted, which is likely caused by their chronic activation. We found that increased frequencies of activated cytokine-producing NK cells are associated with increased disease severity and independently predict poor clinical outcome in patients with ALL. Our studies highlight the benefits of developing NK cell profiling as a diagnostic tool to predict clinical outcome in patients with ALL and underscore the clinical potential of allogeneic NK cell infusions to prevent ALL recurrence., (© 2021 by The American Society of Hematology.)
- Published
- 2021
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11. Signalling input from divergent pathways subverts B cell transformation.
- Author
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Chan LN, Murakami MA, Robinson ME, Caeser R, Sadras T, Lee J, Cosgun KN, Kume K, Khairnar V, Xiao G, Ahmed MA, Aghania E, Deb G, Hurtz C, Shojaee S, Hong C, Pölönen P, Nix MA, Chen Z, Chen CW, Chen J, Vogt A, Heinäniemi M, Lohi O, Wiita AP, Izraeli S, Geng H, Weinstock DM, and Müschen M
- Subjects
- Animals, B-Lymphocytes pathology, Cell Line, Tumor, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases metabolism, Female, Humans, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 6 metabolism, Proto-Oncogene Proteins c-bcl-6 metabolism, Proto-Oncogene Proteins c-myc metabolism, STAT5 Transcription Factor metabolism, B-Lymphocytes cytology, B-Lymphocytes metabolism, Cell Transformation, Neoplastic, Leukemia, B-Cell metabolism, Leukemia, B-Cell pathology, Signal Transduction
- Abstract
Malignant transformation of cells typically involves several genetic lesions, whose combined activity gives rise to cancer
1 . Here we analyse 1,148 patient-derived B-cell leukaemia (B-ALL) samples, and find that individual mutations do not promote leukaemogenesis unless they converge on one single oncogenic pathway that is characteristic of the differentiation stage of transformed B cells. Mutations that are not aligned with this central oncogenic driver activate divergent pathways and subvert transformation. Oncogenic lesions in B-ALL frequently mimic signalling through cytokine receptors at the pro-B-cell stage (via activation of the signal-transduction protein STAT5)2-4 or pre-B-cell receptors in more mature cells (via activation of the protein kinase ERK)5-8 . STAT5- and ERK-activating lesions are found frequently, but occur together in only around 3% of cases (P = 2.2 × 10-16 ). Single-cell mutation and phospho-protein analyses reveal the segregation of oncogenic STAT5 and ERK activation to competing clones. STAT5 and ERK engage opposing biochemical and transcriptional programs that are orchestrated by the transcription factors MYC and BCL6, respectively. Genetic reactivation of the divergent (suppressed) pathway comes at the expense of the principal oncogenic driver and reverses transformation. Conversely, deletion of divergent pathway components accelerates leukaemogenesis. Thus, persistence of divergent signalling pathways represents a powerful barrier to transformation, while convergence on one principal driver defines a central event in leukaemia initiation. Pharmacological reactivation of suppressed divergent circuits synergizes strongly with inhibition of the principal oncogenic driver. Hence, reactivation of divergent pathways can be leveraged as a previously unrecognized strategy to enhance treatment responses.- Published
- 2020
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12. Oncogene-independent BCR-like signaling adaptation confers drug resistance in Ph-like ALL.
- Author
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Hurtz C, Wertheim GB, Loftus JP, Blumenthal D, Lehman A, Li Y, Bagashev A, Manning B, Cummins KD, Burkhardt JK, Perl AE, Carroll M, and Tasian SK
- Subjects
- Animals, Cell Line, Humans, Mice, Dexamethasone pharmacology, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology, Protein Kinase Inhibitors pharmacology, Receptors, Antigen, B-Cell genetics, Receptors, Antigen, B-Cell metabolism, Signal Transduction
- Abstract
Children and adults with Philadelphia chromosome-like B cell acute lymphoblastic leukemia (Ph-like B-ALL) experience high relapse rates despite best-available conventional chemotherapy. Ph-like ALL is driven by genetic alterations that activate constitutive cytokine receptor and kinase signaling, and early-phase trials are investigating the potential of the addition of tyrosine kinase inhibitors (TKIs) to chemotherapy to improve clinical outcomes. However, preclinical studies have shown that JAK or PI3K pathway inhibition is insufficient to eradicate the most common cytokine receptor-like factor 2-rearranged (CRLF2-rearranged) Ph-like ALL subset. We thus sought to define additional essential signaling pathways required in Ph-like leukemogenesis for improved therapeutic targeting. Herein, we describe an adaptive signaling plasticity of CRLF2-rearranged Ph-like ALL following selective TKI pressure, which occurs in the absence of genetic mutations. Interestingly, we observed that Ph-like ALL cells have activated SRC, ERK, and PI3K signaling consistent with activated B cell receptor (BCR) signaling, although they do not express cell surface μ-heavy chain (μHC). Combinatorial targeting of JAK/STAT, PI3K, and "BCR-like" signaling with multiple TKIs and/or dexamethasone prevented this signaling plasticity and induced complete cell death, demonstrating a more optimal and clinically pragmatic therapeutic strategy for CRLF2-rearranged Ph-like ALL.
- Published
- 2020
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13. Rationale for targeting BCL6 in MLL -rearranged acute lymphoblastic leukemia.
- Author
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Hurtz C, Chan LN, Geng H, Ballabio E, Xiao G, Deb G, Khoury H, Chen CW, Armstrong SA, Chen J, Ernst P, Melnick A, Milne T, and Müschen M
- Subjects
- Animals, Biomarkers, Tumor genetics, Cell Survival genetics, Cells, Cultured, Gene Deletion, Gene Targeting, Humans, Mice, Oncogene Proteins, Fusion genetics, Oncogene Proteins, Fusion metabolism, Prognosis, Promoter Regions, Genetic genetics, Gene Expression Regulation, Leukemic, Myeloid-Lymphoid Leukemia Protein genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma physiopathology, Proto-Oncogene Proteins c-bcl-6 genetics, Proto-Oncogene Proteins c-bcl-6 metabolism
- Abstract
Chromosomal rearrangements of the mixed lineage leukemia ( MLL ) gene occur in ∼10% of B-cell acute lymphoblastic leukemia (B-ALL) and define a group of patients with dismal outcomes. Immunohistochemical staining of bone marrow biopsies from most of these patients revealed aberrant expression of BCL6, a transcription factor that promotes oncogenic B-cell transformation and drug resistance in B-ALL. Our genetic and ChIP-seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) analyses showed that MLL-AF4 and MLL-ENL fusions directly bound to the BCL6 promoter and up-regulated BCL6 expression. While oncogenic MLL fusions strongly induced aberrant BCL6 expression in B-ALL cells, germline MLL was required to up-regulate Bcl6 in response to physiological stimuli during normal B-cell development. Inducible expression of Bcl6 increased MLL mRNA levels, which was reversed by genetic deletion and pharmacological inhibition of Bcl6, suggesting a positive feedback loop between MLL and BCL6. Highlighting the central role of BCL6 in MLL- rearranged B-ALL, conditional deletion and pharmacological inhibition of BCL6 compromised leukemogenesis in transplant recipient mice and restored sensitivity to vincristine chemotherapy in MLL- rearranged B-ALL patient samples. Oncogenic MLL fusions strongly induced transcriptional activation of the proapoptotic BH3-only molecule BIM, while BCL6 was required to curb MLL-induced expression of BIM. Notably, peptide (RI-BPI) and small molecule (FX1) BCL6 inhibitors derepressed BIM and synergized with the BH3-mimetic ABT-199 in eradicating MLL- rearranged B-ALL cells. These findings uncover MLL-dependent transcriptional activation of BCL6 as a previously unrecognized requirement of malignant transformation by oncogenic MLL fusions and identified BCL6 as a novel target for the treatment of MLL-rearranged B-ALL., (© 2019 Hurtz et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2019
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14. Author Correction: Metabolic gatekeeper function of B-lymphoid transcription factors.
- Author
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Chan LN, Chen Z, Braas D, Lee JW, Xiao G, Geng H, Cosgun KN, Hurtz C, Shojaee S, Cazzaniga V, Schjerven H, Ernst T, Hochhaus A, Kornblau SM, Konopleva M, Pufall MA, Cazzaniga G, Liu GJ, Milne TA, Koeffler HP, Ross TS, Sánchez-García I, Borkhardt A, Yamamoto KR, Dickins RA, Graeber TG, and Müschen M
- Abstract
In Fig. 3c of this Letter, the the effects of CRISPR-Cas9-mediated deletion of NR3C1, TXNIP and CNR2 in patient-derived B-lineage leukaemia cells were shown. For curves depicting NR3C1 (left graph), data s for TXNIP (middle graph) were inadvertently plotted. This figure has been corrected online, and the original Fig. 3c is shown as Supplementary Information to this Amendment for transparency. The error does not affect the conclusions of the Letter. In addition, Source Data files have been added for the Figs. 1-4 and Extended Data Figs. 1-10 of the original Letter.
- Published
- 2018
- Full Text
- View/download PDF
15. Extrafollicular CD4 + T-B interactions are sufficient for inducing autoimmune-like chronic graft-versus-host disease.
- Author
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Deng R, Hurtz C, Song Q, Yue C, Xiao G, Yu H, Wu X, Muschen M, Forman S, Martin PJ, and Zeng D
- Subjects
- Animals, Chronic Disease, Germinal Center cytology, Graft vs Host Disease genetics, Humans, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Proto-Oncogene Proteins c-bcl-6 genetics, Proto-Oncogene Proteins c-bcl-6 immunology, STAT3 Transcription Factor genetics, STAT3 Transcription Factor immunology, T-Lymphocytes, Helper-Inducer immunology, Autoimmune Diseases immunology, B-Lymphocytes immunology, CD4-Positive T-Lymphocytes immunology, Germinal Center immunology, Graft vs Host Disease immunology
- Abstract
Chronic graft-versus-host disease (cGVHD) is an autoimmune-like syndrome mediated by pathogenic CD4
+ T and B cells, but the function of extrafollicular and germinal center CD4+ T and B interactions in cGVHD pathogenesis remains largely unknown. Here we show that extrafollicular CD4+ T and B interactions are sufficient for inducing cGVHD, while germinal center formation is dispensable. The pathogenesis of cGVHD is associated with the expansion of extrafollicular CD44hi CD62lo PSGL-1lo CD4+ (PSGL-1lo CD4+ ) T cells. These cells express high levels of ICOS, and the blockade of ICOS/ICOSL interaction prevents their expansion and ameliorates cGVHD. Expansion of PSGL-1lo CD4+ T cells is also prevented by BCL6 or Stat3 deficiency in donor CD4+ T cells, with the induction of cGVHD ameliorated by BCL6 deficiency and completely suppressed by Stat3 deficiency in donor CD4+ T cells. These results support that Stat3- and BCL6-dependent extrafollicular CD4+ T and B interactions play critical functions in the pathogenesis of cGVHD.Chronic graft-versus-host disease (cGVHD) is mediated by specific CD4 and B cells, but the relative contribution of extrafollicular and germinal centre (GC) T-B interaction is unclear. Here the authors show that the extrafollicular expansion of a specific CD4 T subset is sufficient for inducing cGVHD while GC is dispensable.- Published
- 2017
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16. Ibrutinib inhibits pre-BCR + B-cell acute lymphoblastic leukemia progression by targeting BTK and BLK.
- Author
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Kim E, Hurtz C, Koehrer S, Wang Z, Balasubramanian S, Chang BY, Müschen M, Davis RE, and Burger JA
- Subjects
- Adenine analogs & derivatives, Agammaglobulinaemia Tyrosine Kinase, Animals, Blotting, Western, Cell Line, Tumor, Cell Proliferation drug effects, Flow Cytometry, Gene Expression Profiling, Gene Knockout Techniques, Humans, Mice, Piperidines, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma enzymology, Protein-Tyrosine Kinases pharmacology, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology, Protein-Tyrosine Kinases antagonists & inhibitors, Pyrazoles pharmacology, Pyrimidines pharmacology, src-Family Kinases antagonists & inhibitors
- Abstract
Targeting B-cell receptor (BCR) signaling is a successful therapeutic strategy in mature B-cell malignancies. Precursor BCR (pre-BCR) signaling, which is critical during normal B lymphopoiesis, also plays an important role in pre-BCR
+ B cell acute lymphoblastic leukemia (B-ALL). Here, we investigated the activity and mechanism of action of the BTK inhibitor ibrutinib in preclinical models of B-ALL. Pre-BCR+ ALL cells were exquisitely sensitive to ibrutinib at therapeutically relevant drug concentrations. In pre-BCR+ ALL, ibrutinib thwarted autonomous and induced pre-BCR signaling, resulting in deactivation of PI3K/Akt signaling. Ibrutinib modulated the expression of pre-BCR regulators (PTPN6, CD22, CD72, and PKCβ) and substantially reduced BCL6 levels. Ibrutinib inhibited ALL cell migration toward CXCL12 and beneath marrow stromal cells and reduced CD44 expression. CRISPR-Cas9 gene editing revealed that both BTK and B lymphocyte kinase (BLK) are relevant targets of ibrutinib in pre-BCR+ ALL. Consequently, in mouse xenograft models of pre-BCR+ ALL, ibrutinib treatment significantly prolonged survival. Combination treatment of ibrutinib with dexamethasone or vincristine demonstrated synergistic activity against pre-BCR+ ALL. These data corroborate ibrutinib as a promising targeted agent for pre-BCR+ ALL and highlight the importance of ibrutinib effects on alternative kinase targets., (© 2017 by The American Society of Hematology.)- Published
- 2017
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17. Metabolic gatekeeper function of B-lymphoid transcription factors.
- Author
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Chan LN, Chen Z, Braas D, Lee JW, Xiao G, Geng H, Cosgun KN, Hurtz C, Shojaee S, Cazzaniga V, Schjerven H, Ernst T, Hochhaus A, Kornblau SM, Konopleva M, Pufall MA, Cazzaniga G, Liu GJ, Milne TA, Koeffler HP, Ross TS, Sánchez-García I, Borkhardt A, Yamamoto KR, Dickins RA, Graeber TG, and Müschen M
- Subjects
- AMP-Activated Protein Kinase Kinases, AMP-Activated Protein Kinases antagonists & inhibitors, Adenosine Triphosphate metabolism, Animals, B-Lymphocytes drug effects, Carcinogenesis genetics, Carrier Proteins agonists, Carrier Proteins metabolism, Cell Death, Chromatin Immunoprecipitation, Citric Acid Cycle, Disease Models, Animal, Female, Glucocorticoids pharmacology, Glucocorticoids therapeutic use, Humans, Ikaros Transcription Factor metabolism, Mice, Mice, Transgenic, PAX5 Transcription Factor deficiency, PAX5 Transcription Factor genetics, PAX5 Transcription Factor metabolism, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology, Protein Serine-Threonine Kinases metabolism, Pyruvic Acid metabolism, Receptor, Cannabinoid, CB2 agonists, Receptor, Cannabinoid, CB2 metabolism, Receptors, Glucocorticoid metabolism, Sequence Analysis, RNA, B-Lymphocytes metabolism, Energy Metabolism genetics, Gene Expression Regulation, Neoplastic, Glucose metabolism, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Transcription Factors metabolism
- Abstract
B-lymphoid transcription factors, such as PAX5 and IKZF1, are critical for early B-cell development, yet lesions of the genes encoding these transcription factors occur in over 80% of cases of pre-B-cell acute lymphoblastic leukaemia (ALL). The importance of these lesions in ALL has, until now, remained unclear. Here, by combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, we identify a novel B-lymphoid program for transcriptional repression of glucose and energy supply. Our metabolic analyses revealed that PAX5 and IKZF1 enforce a state of chronic energy deprivation, resulting in constitutive activation of the energy-stress sensor AMPK. Dominant-negative mutants of PAX5 and IKZF1, however, relieved this glucose and energy restriction. In a transgenic pre-B ALL mouse model, the heterozygous deletion of Pax5 increased glucose uptake and ATP levels by more than 25-fold. Reconstitution of PAX5 and IKZF1 in samples from patients with pre-B ALL restored a non-permissive state and induced energy crisis and cell death. A CRISPR/Cas9-based screen of PAX5 and IKZF1 transcriptional targets identified the products of NR3C1 (encoding the glucocorticoid receptor), TXNIP (encoding a glucose-feedback sensor) and CNR2 (encoding a cannabinoid receptor) as central effectors of B-lymphoid restriction of glucose and energy supply. Notably, transport-independent lipophilic methyl-conjugates of pyruvate and tricarboxylic acid cycle metabolites bypassed the gatekeeper function of PAX5 and IKZF1 and readily enabled leukaemic transformation. Conversely, pharmacological TXNIP and CNR2 agonists and a small-molecule AMPK inhibitor strongly synergized with glucocorticoids, identifying TXNIP, CNR2 and AMPK as potential therapeutic targets. Furthermore, our results provide a mechanistic explanation for the empirical finding that glucocorticoids are effective in the treatment of B-lymphoid but not myeloid malignancies. Thus, B-lymphoid transcription factors function as metabolic gatekeepers by limiting the amount of cellular ATP to levels that are insufficient for malignant transformation.
- Published
- 2017
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18. Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures.
- Author
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Graham NA, Minasyan A, Lomova A, Cass A, Balanis NG, Friedman M, Chan S, Zhao S, Delgado A, Go J, Beck L, Hurtz C, Ng C, Qiao R, Ten Hoeve J, Palaskas N, Wu H, Müschen M, Multani AS, Port E, Larson SM, Schultz N, Braas D, Christofk HR, Mellinghoff IK, and Graeber TG
- Subjects
- Cell Line, Tumor, Evolution, Molecular, Gene Amplification, Gene Deletion, Gene Expression Regulation, Neoplastic, Genomic Instability, Humans, Metabolic Networks and Pathways, Principal Component Analysis, Selection, Genetic, DNA Copy Number Variations, Gene Expression Profiling methods, Glycolysis, Neoplasms genetics
- Abstract
Copy number alteration (CNA) profiling of human tumors has revealed recurrent patterns of DNA amplifications and deletions across diverse cancer types. These patterns are suggestive of conserved selection pressures during tumor evolution but cannot be fully explained by known oncogenes and tumor suppressor genes. Using a pan-cancer analysis of CNA data from patient tumors and experimental systems, here we show that principal component analysis-defined CNA signatures are predictive of glycolytic phenotypes, including
18 F-fluorodeoxy-glucose (FDG) avidity of patient tumors, and increased proliferation. The primary CNA signature is enriched for p53 mutations and is associated with glycolysis through coordinate amplification of glycolytic genes and other cancer-linked metabolic enzymes. A pan-cancer and cross-species comparison of CNAs highlighted 26 consistently altered DNA regions, containing 11 enzymes in the glycolysis pathway in addition to known cancer-driving genes. Furthermore, exogenous expression of hexokinase and enolase enzymes in an experimental immortalization system altered the subsequent copy number status of the corresponding endogenous loci, supporting the hypothesis that these metabolic genes act as drivers within the conserved CNA amplification regions. Taken together, these results demonstrate that metabolic stress acts as a selective pressure underlying the recurrent CNAs observed in human tumors, and further cast genomic instability as an enabling event in tumorigenesis and metabolic evolution., (© 2017 The Authors. Published under the terms of the CC BY 4.0 license.)- Published
- 2017
- Full Text
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19. Erk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia.
- Author
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Shojaee S, Caeser R, Buchner M, Park E, Swaminathan S, Hurtz C, Geng H, Chan LN, Klemm L, Hofmann WK, Qiu YH, Zhang N, Coombes KR, Paietta E, Molkentin J, Koeffler HP, Willman CL, Hunger SP, Melnick A, Kornblau SM, and Müschen M
- Subjects
- Animals, Antineoplastic Agents pharmacology, Cell Transformation, Neoplastic metabolism, Cell Transformation, Neoplastic pathology, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Dual Specificity Phosphatase 6 genetics, Dual Specificity Phosphatase 6 metabolism, Host Cell Factor C1, Humans, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Membrane Proteins antagonists & inhibitors, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Mice, Transgenic, Molecular Sequence Data, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Prognosis, Protein Serine-Threonine Kinases, Small Molecule Libraries pharmacology, Transcription Factors genetics, Transcription Factors metabolism, Cell Transformation, Neoplastic genetics, MAP Kinase Signaling System drug effects, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology
- Abstract
Studying mechanisms of malignant transformation of human pre-B cells, we found that acute activation of oncogenes induced immediate cell death in the vast majority of cells. Few surviving pre-B cell clones had acquired permissiveness to oncogenic signaling by strong activation of negative feedback regulation of Erk signaling. Studying negative feedback regulation of Erk in genetic experiments at three different levels, we found that Spry2, Dusp6, and Etv5 were essential for oncogenic transformation in mouse models for pre-B acute lymphoblastic leukemia (ALL). Interestingly, a small molecule inhibitor of DUSP6 selectively induced cell death in patient-derived pre-B ALL cells and overcame conventional mechanisms of drug-resistance., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
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20. Self-enforcing feedback activation between BCL6 and pre-B cell receptor signaling defines a distinct subtype of acute lymphoblastic leukemia.
- Author
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Geng H, Hurtz C, Lenz KB, Chen Z, Baumjohann D, Thompson S, Goloviznina NA, Chen WY, Huan J, LaTocha D, Ballabio E, Xiao G, Lee JW, Deucher A, Qi Z, Park E, Huang C, Nahar R, Kweon SM, Shojaee S, Chan LN, Yu J, Kornblau SM, Bijl JJ, Ye BH, Ansel KM, Paietta E, Melnick A, Hunger SP, Kurre P, Tyner JW, Loh ML, Roeder RG, Druker BJ, Burger JA, Milne TA, Chang BH, and Müschen M
- Subjects
- Basic Helix-Loop-Helix Transcription Factors metabolism, Basic Helix-Loop-Helix Transcription Factors physiology, Clinical Trials as Topic, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Humans, Intracellular Signaling Peptides and Proteins metabolism, Molecular Sequence Data, Phosphatidylinositol 3-Kinase metabolism, Pre-B-Cell Leukemia Transcription Factor 1, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Protein-Tyrosine Kinases metabolism, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins physiology, Proto-Oncogene Proteins c-bcl-6, Signal Transduction, Syk Kinase, Up-Regulation, src-Family Kinases metabolism, DNA-Binding Proteins physiology, Gene Expression Regulation, Neoplastic, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor Cells, B-Lymphoid metabolism
- Abstract
Studying 830 pre-B ALL cases from four clinical trials, we found that human ALL can be divided into two fundamentally distinct subtypes based on pre-BCR function. While absent in the majority of ALL cases, tonic pre-BCR signaling was found in 112 cases (13.5%). In these cases, tonic pre-BCR signaling induced activation of BCL6, which in turn increased pre-BCR signaling output at the transcriptional level. Interestingly, inhibition of pre-BCR-related tyrosine kinases reduced constitutive BCL6 expression and selectively killed patient-derived pre-BCR(+) ALL cells. These findings identify a genetically and phenotypically distinct subset of human ALL that critically depends on tonic pre-BCR signaling. In vivo treatment studies suggested that pre-BCR tyrosine kinase inhibitors are useful for the treatment of patients with pre-BCR(+) ALL., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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21. Mechanistic rationale for targeting the unfolded protein response in pre-B acute lymphoblastic leukemia.
- Author
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Kharabi Masouleh B, Geng H, Hurtz C, Chan LN, Logan AC, Chang MS, Huang C, Swaminathan S, Sun H, Paietta E, Melnick AM, Koeffler P, and Müschen M
- Subjects
- Adult, Animals, B-Lymphocytes metabolism, Base Sequence, Basic-Leucine Zipper Transcription Factors pharmacology, Blotting, Western, Cell Differentiation physiology, Child, Chromatin Immunoprecipitation, DNA-Binding Proteins genetics, DNA-Binding Proteins pharmacology, Endoplasmic Reticulum Chaperone BiP, Endoplasmic Reticulum Stress physiology, Endoribonucleases genetics, Flow Cytometry, Gene Deletion, Heat-Shock Proteins genetics, Heat-Shock Proteins metabolism, Heterografts, Humans, Kaplan-Meier Estimate, Mice, Microarray Analysis, Molecular Sequence Data, Positive Regulatory Domain I-Binding Factor 1, Protein Serine-Threonine Kinases genetics, Proto-Oncogene Proteins c-bcl-6, Real-Time Polymerase Chain Reaction, Regulatory Factor X Transcription Factors, Repressor Proteins genetics, Repressor Proteins metabolism, Sequence Analysis, RNA, Transcription Factors genetics, Unfolded Protein Response physiology, X-Box Binding Protein 1, beta-Galactosidase, B-Lymphocytes physiology, DNA-Binding Proteins metabolism, Endoplasmic Reticulum Stress drug effects, Endoribonucleases metabolism, Gene Expression Regulation drug effects, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Protein Serine-Threonine Kinases metabolism, Transcription Factors metabolism, Unfolded Protein Response drug effects
- Abstract
The unfolded protein response (UPR) pathway, a stress-induced signaling cascade emanating from the endoplasmic reticulum (ER), regulates the expression and activity of molecules including BiP (HSPA5), IRE1 (ERN1), Blimp-1 (PRDM1), and X-box binding protein 1 (XBP1). These molecules are required for terminal differentiation of B cells into plasma cells and expressed at high levels in plasma cell-derived multiple myeloma. Although these molecules have no known role at early stages of B-cell development, here we show that their expression transiently peaks at the pre-B-cell receptor checkpoint. Inducible, Cre-mediated deletion of Hspa5, Prdm1, and Xbp1 consistently induces cellular stress and cell death in normal pre-B cells and in pre-B-cell acute lymphoblastic leukemia (ALL) driven by BCR-ABL1- and NRAS(G12D) oncogenes. Mechanistically, expression and activity of the UPR downstream effector XBP1 is regulated positively by STAT5 and negatively by the B-cell-specific transcriptional repressors BACH2 and BCL6. In two clinical trials for children and adults with ALL, high XBP1 mRNA levels at the time of diagnosis predicted poor outcome. A small molecule inhibitor of ERN1-mediated XBP1 activation induced selective cell death of patient-derived pre-B ALL cells in vitro and significantly prolonged survival of transplant recipient mice in vivo. Collectively, these studies reveal that pre-B ALL cells are uniquely vulnerable to ER stress and identify the UPR pathway and its downstream effector XBP1 as novel therapeutic targets to overcome drug resistance in pre-B ALL.
- Published
- 2014
- Full Text
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22. BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint.
- Author
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Swaminathan S, Huang C, Geng H, Chen Z, Harvey R, Kang H, Ng C, Titz B, Hurtz C, Sadiyah MF, Nowak D, Thoennissen GB, Rand V, Graeber TG, Koeffler HP, Carroll WL, Willman CL, Hall AG, Igarashi K, Melnick A, and Müschen M
- Subjects
- Animals, Basic-Leucine Zipper Transcription Factors genetics, Cell Death, Cell Differentiation genetics, Cell Survival genetics, Cell Transformation, Neoplastic pathology, DNA-Binding Proteins metabolism, Gene Deletion, Gene Expression Regulation, Leukemic, Green Fluorescent Proteins metabolism, Immunoglobulin mu-Chains metabolism, Mice, Molecular Sequence Data, PAX5 Transcription Factor metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Precursor Cells, B-Lymphoid metabolism, Precursor Cells, B-Lymphoid pathology, Proto-Oncogene Proteins c-bcl-6, Proto-Oncogene Proteins c-myc metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, STAT5 Transcription Factor metabolism, Treatment Outcome, V(D)J Recombination genetics, Basic-Leucine Zipper Transcription Factors metabolism, Pre-B Cell Receptors metabolism, Tumor Suppressor Protein p53 metabolism
- Abstract
The B cell-specific transcription factor BACH2 is required for affinity maturation of B cells. Here we show that Bach2-mediated activation of p53 is required for stringent elimination of pre-B cells that failed to productively rearrange immunoglobulin VH-DJH gene segments. After productive VH-DJH gene rearrangement, pre-B cell receptor signaling ends BACH2-mediated negative selection through B cell lymphoma 6 (BCL6)-mediated repression of p53. In patients with pre-B acute lymphoblastic leukemia, the BACH2-mediated checkpoint control is compromised by deletions, rare somatic mutations and loss of its upstream activator, PAX5. Low levels of BACH2 expression in these patients represent a strong independent predictor of poor clinical outcome. In this study, we demonstrate that Bach2(+/+) pre-B cells resist leukemic transformation by Myc through Bach2-dependent upregulation of p53 and do not initiate fatal leukemia in transplant-recipient mice. Chromatin immunoprecipitation sequencing and gene expression analyses carried out by us revealed that BACH2 competes with BCL6 for promoter binding and reverses BCL6-mediated repression of p53 and other cell cycle checkpoint-control genes. These findings identify BACH2 as a crucial mediator of negative selection at the pre-B cell receptor checkpoint and a safeguard against leukemogenesis.
- Published
- 2013
- Full Text
- View/download PDF
23. O-acetylated N-acetylneuraminic acid as a novel target for therapy in human pre-B acute lymphoblastic leukemia.
- Author
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Parameswaran R, Lim M, Arutyunyan A, Abdel-Azim H, Hurtz C, Lau K, Müschen M, Yu RK, von Itzstein M, Heisterkamp N, and Groffen J
- Subjects
- Acetylation, Animals, Antineoplastic Agents, Phytogenic therapeutic use, Antineoplastic Agents, Phytogenic urine, Cell Survival, Female, Fibroblasts metabolism, Fibroblasts pathology, Humans, Male, Mice, N-Acetylneuraminic Acid genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology, Pyrimidines therapeutic use, Vincristine therapeutic use, Drug Resistance, Neoplasm, N-Acetylneuraminic Acid metabolism, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma metabolism
- Abstract
The development of resistance to chemotherapy is a major cause of relapse in acute lymphoblastic leukemia (ALL). Though several mechanisms associated with drug resistance have been studied in detail, the role of carbohydrate modification remains unexplored. Here, we investigated the contribution of 9-O-acetylated N-acetylneuraminic acid (Neu5Ac) to survival and drug resistance development in ALL cells. A strong induction of 9-O-acetylated Neu5Ac including 9-O-acetyl GD3 was detected in ALL cells that developed resistance against vincristine or nilotinib, drugs with distinct cytotoxic mechanisms. Removal of 9-O-acetyl residues from Neu5Ac on the cell surface by an O-acetylesterase made ALL cells more vulnerable to such drugs. Moreover, removal of intracellular and cell surface-resident 9-O-acetyl Neu5Ac by lentiviral transduction of the esterase was lethal to ALL cells in vitro even in the presence of stromal protection. Interestingly, expression of the esterase in normal fibroblasts or endothelial cells had no effect on their survival. Transplanted mice induced for expression of the O-acetylesterase in the ALL cells exhibited a reduction of leukemia to minimal cell numbers and significantly increased survival. This demonstrates that Neu5Ac 9-O-acetylation is essential for survival of these cells and suggests that Neu5Ac de-O-acetylation could be used as therapy to eradicate drug-resistant ALL cells.
- Published
- 2013
- Full Text
- View/download PDF
24. SOX4 enables oncogenic survival signals in acute lymphoblastic leukemia.
- Author
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Ramezani-Rad P, Geng H, Hurtz C, Chan LN, Chen Z, Jumaa H, Melnick A, Paietta E, Carroll WL, Willman CL, Lefebvre V, and Müschen M
- Subjects
- Animals, B-Lymphocytes drug effects, B-Lymphocytes metabolism, Benzamides, Cell Survival drug effects, Child, DNA Methylation, Humans, Imatinib Mesylate, Kaplan-Meier Estimate, Mice, Mice, Inbred NOD, Mice, SCID, Multicenter Studies as Topic statistics & numerical data, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins biosynthesis, Neoplasm Proteins genetics, Neoplasm Proteins physiology, Piperazines pharmacology, Piperazines therapeutic use, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma mortality, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology, Promoter Regions, Genetic, Proportional Hazards Models, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Pyrimidines pharmacology, Pyrimidines therapeutic use, Radiation Chimera, Randomized Controlled Trials as Topic statistics & numerical data, SOXC Transcription Factors biosynthesis, SOXC Transcription Factors deficiency, SOXC Transcription Factors genetics, Signal Transduction drug effects, Tumor Cells, Cultured cytology, Tumor Cells, Cultured drug effects, Tumor Stem Cell Assay, Gene Expression Regulation, Leukemic genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, SOXC Transcription Factors physiology, Signal Transduction physiology
- Abstract
The Sox4 transcription factor mediates early B-cell differentiation. Compared with normal pre-B cells, SOX4 promoter regions in Ph(+) ALL cells are significantly hypomethylated. Loss and gain-of-function experiments identified Sox4 as a critical activator of PI3K/AKT and MAPK signaling in ALL cells. ChIP experiments confirmed that SOX4 binds to and transcriptionally activates promoters of multiple components within the PI3K/AKT and MAPK signaling pathways. Cre-mediated deletion of Sox4 had little effect on normal pre-B cells but compromised proliferation and viability of leukemia cells, which was rescued by BCL2L1 and constitutively active AKT and p110 PI3K. Consistent with these findings, high levels of SOX4 expression in ALL cells at the time of diagnosis predicted poor outcome in a pediatric clinical trial (COG P9906). Collectively, these studies identify SOX4 as a central mediator of oncogenic PI3K/AKT and MAPK signaling in ALL.
- Published
- 2013
- Full Text
- View/download PDF
25. Integrative epigenomic analysis identifies biomarkers and therapeutic targets in adult B-acute lymphoblastic leukemia.
- Author
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Geng H, Brennan S, Milne TA, Chen WY, Li Y, Hurtz C, Kweon SM, Zickl L, Shojaee S, Neuberg D, Huang C, Biswas D, Xin Y, Racevskis J, Ketterling RP, Luger SM, Lazarus H, Tallman MS, Rowe JM, Litzow MR, Guzman ML, Allis CD, Roeder RG, Müschen M, Paietta E, Elemento O, and Melnick AM
- Subjects
- Biomarkers, Tumor analysis, Biomarkers, Tumor metabolism, CD3 Complex biosynthesis, DNA Methylation, DNA-Binding Proteins genetics, Epigenomics, Fusion Proteins, bcr-abl genetics, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Histone-Lysine N-Methyltransferase, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Humans, Interleukin-2 Receptor alpha Subunit genetics, Myeloid-Lymphoid Leukemia Protein genetics, Oncogene Proteins, Fusion genetics, Oncogene Proteins, Fusion metabolism, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology, Promoter Regions, Genetic, Proto-Oncogene Proteins c-bcl-6, Biomarkers, Tumor genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
Unlabelled: Genetic lesions such as BCR-ABL1, E2A-PBX1, and MLL rearrangements (MLLr) are associated with unfavorable outcomes in adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Leukemia oncoproteins may directly or indirectly disrupt cytosine methylation patterning to mediate the malignant phenotype. We postulated that DNA methylation signatures in these aggressive B-ALLs would point toward disease mechanisms and useful biomarkers and therapeutic targets. We therefore conducted DNA methylation and gene expression profiling on a cohort of 215 adult patients with B-ALL enrolled in a single phase III clinical trial (ECOG E2993) and normal control B cells. In BCR-ABL1-positive B-ALLs, aberrant cytosine methylation patterning centered around a cytokine network defined by hypomethylation and overexpression of IL2RA(CD25). The E2993 trial clinical data showed that CD25 expression was strongly associated with a poor outcome in patients with ALL regardless of BCR-ABL1 status, suggesting CD25 as a novel prognostic biomarker for risk stratification in B-ALLs. In E2A-PBX1-positive B-ALLs, aberrant DNA methylation patterning was strongly associated with direct fusion protein binding as shown by the E2A-PBX1 chromatin immunoprecipitation (ChIP) sequencing (ChIP-seq), suggesting that E2A-PBX1 fusion protein directly remodels the epigenome to impose an aggressive B-ALL phenotype. MLLr B-ALL featured prominent cytosine hypomethylation, which was linked with MLL fusion protein binding, H3K79 dimethylation, and transcriptional upregulation, affecting a set of known and newly identified MLL fusion direct targets with oncogenic activity such as FLT3 and BCL6. Notably, BCL6 blockade or loss of function suppressed proliferation and survival of MLLr leukemia cells, suggesting BCL6-targeted therapy as a new therapeutic strategy for MLLr B-ALLs., Significance: We conducted the first integrative epigenomic study in adult B-ALLs, as a correlative study to the ECOG E2993 phase III clinical trial. This study links for the first time the direct actions of oncogenic fusion proteins with disruption of epigenetic regulation mediated by cytosine methylation. We identify a novel clinically actionable biomarker in B-ALLs: IL2RA (CD25), which is linked with BCR-ABL1 and an inflammatory signaling network associated with chemotherapy resistance. We show that BCL6 is a novel MLL fusion protein target that is required to maintain the proliferation and survival of primary human adult MLLr cells and provide the basis for a clinical trial with BCL6 inhibitors for patients with MLLr., (©2012 AACR.)
- Published
- 2012
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26. BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia.
- Author
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Hurtz C, Hatzi K, Cerchietti L, Braig M, Park E, Kim YM, Herzog S, Ramezani-Rad P, Jumaa H, Müller MC, Hofmann WK, Hochhaus A, Ye BH, Agarwal A, Druker BJ, Shah NP, Melnick AM, and Müschen M
- Subjects
- Animals, Antigens, CD34 metabolism, Benzamides, DNA-Binding Proteins antagonists & inhibitors, DNA-Binding Proteins genetics, Disease Models, Animal, Forkhead Transcription Factors metabolism, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells physiology, Humans, Imatinib Mesylate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Mice, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Neoplasm Transplantation, Piperazines therapeutic use, Protein Kinase Inhibitors therapeutic use, Protein-Tyrosine Kinases antagonists & inhibitors, Proto-Oncogene Proteins c-bcl-6, Pyrimidines therapeutic use, Tumor Cells, Cultured, Tumor Suppressor Protein p53 genetics, Cell Survival, DNA-Binding Proteins metabolism, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive physiopathology, Neoplastic Stem Cells physiology, Tumor Suppressor Protein p53 metabolism
- Abstract
Chronic myeloid leukemia (CML) is induced by the oncogenic BCR-ABL1 tyrosine kinase and can be effectively treated for many years with tyrosine kinase inhibitors (TKIs). However, unless CML patients receive life-long TKI treatment, leukemia will eventually recur; this is attributed to the failure of TKI treatment to eradicate leukemia-initiating cells (LICs). Recent work demonstrated that FoxO factors are critical for maintenance of CML-initiating cells; however, the mechanism of FoxO-dependent leukemia initiation remained elusive. Here, we identified the BCL6 protooncogene as a critical effector downstream of FoxO in self-renewal signaling of CML-initiating cells. BCL6 represses Arf and p53 in CML cells and is required for colony formation and initiation of leukemia. Importantly, peptide inhibition of BCL6 in human CML cells compromises colony formation and leukemia initiation in transplant recipients and selectively eradicates CD34(+) CD38(-) LICs in patient-derived CML samples. These findings suggest that pharmacological inhibition of BCL6 may represent a novel strategy to eradicate LICs in CML. Clinical validation of this concept could limit the duration of TKI treatment in CML patients, which is currently life-long, and substantially decrease the risk of blast crisis transformation.
- Published
- 2011
- Full Text
- View/download PDF
27. BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition.
- Author
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Duy C, Hurtz C, Shojaee S, Cerchietti L, Geng H, Swaminathan S, Klemm L, Kweon SM, Nahar R, Braig M, Park E, Kim YM, Hofmann WK, Herzog S, Jumaa H, Koeffler HP, Yu JJ, Heisterkamp N, Graeber TG, Wu H, Ye BH, Melnick A, and Müschen M
- Subjects
- ADP-Ribosylation Factor 1 metabolism, Animals, Cell Survival drug effects, DNA-Binding Proteins biosynthesis, DNA-Binding Proteins deficiency, DNA-Binding Proteins genetics, Gene Expression Regulation, Neoplastic drug effects, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins c-bcl-6, Transcription, Genetic, Tumor Suppressor Protein p53 metabolism, DNA-Binding Proteins metabolism, Drug Resistance, Neoplasm, Fusion Proteins, bcr-abl antagonists & inhibitors, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Protein Kinase Inhibitors pharmacology
- Abstract
Tyrosine kinase inhibitors (TKIs) are widely used to treat patients with leukaemia driven by BCR-ABL1 (ref. 1) and other oncogenic tyrosine kinases. Recent efforts have focused on developing more potent TKIs that also inhibit mutant tyrosine kinases. However, even effective TKIs typically fail to eradicate leukaemia-initiating cells (LICs), which often cause recurrence of leukaemia after initially successful treatment. Here we report the discovery of a novel mechanism of drug resistance, which is based on protective feedback signalling of leukaemia cells in response to treatment with TKI. We identify BCL6 as a central component of this drug-resistance pathway and demonstrate that targeted inhibition of BCL6 leads to eradication of drug-resistant and leukaemia-initiating subclones.
- Published
- 2011
- Full Text
- View/download PDF
28. BCL6 is critical for the development of a diverse primary B cell repertoire.
- Author
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Duy C, Yu JJ, Nahar R, Swaminathan S, Kweon SM, Polo JM, Valls E, Klemm L, Shojaee S, Cerchietti L, Schuh W, Jäck HM, Hurtz C, Ramezani-Rad P, Herzog S, Jumaa H, Koeffler HP, de Alborán IM, Melnick AM, Ye BH, and Müschen M
- Subjects
- ADP-Ribosylation Factors metabolism, Animals, Apoptosis, Base Sequence, Cell Proliferation, Cell Survival, Cells, Cultured, Cytoprotection, DNA Damage genetics, Down-Regulation genetics, Gene Rearrangement, B-Lymphocyte, Light Chain genetics, Humans, Interleukin-7 metabolism, Lymphopoiesis, Mice, Molecular Sequence Data, Pre-B Cell Receptors metabolism, Precursor Cells, B-Lymphoid cytology, Precursor Cells, B-Lymphoid metabolism, Proto-Oncogene Proteins c-bcl-6, Proto-Oncogene Proteins c-myc metabolism, Recombination, Genetic genetics, Signal Transduction, Transcription, Genetic, Up-Regulation genetics, B-Lymphocytes cytology, B-Lymphocytes immunology, DNA-Binding Proteins immunology
- Abstract
BCL6 protects germinal center (GC) B cells against DNA damage-induced apoptosis during somatic hypermutation and class-switch recombination. Although expression of BCL6 was not found in early IL-7-dependent B cell precursors, we report that IL-7Ralpha-Stat5 signaling negatively regulates BCL6. Upon productive VH-DJH gene rearrangement and expression of a mu heavy chain, however, activation of pre-B cell receptor signaling strongly induces BCL6 expression, whereas IL-7Ralpha-Stat5 signaling is attenuated. At the transition from IL-7-dependent to -independent stages of B cell development, BCL6 is activated, reaches expression levels resembling those in GC B cells, and protects pre-B cells from DNA damage-induced apoptosis during immunoglobulin (Ig) light chain gene recombination. In the absence of BCL6, DNA breaks during Ig light chain gene rearrangement lead to excessive up-regulation of Arf and p53. As a consequence, the pool of new bone marrow immature B cells is markedly reduced in size and clonal diversity. We conclude that negative regulation of Arf by BCL6 is required for pre-B cell self-renewal and the formation of a diverse polyclonal B cell repertoire.
- Published
- 2010
- Full Text
- View/download PDF
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