25 results on '"Claudiu V. Cotta"'
Search Results
2. T-cell large granular lymphocytic leukemia associated with inclusion body myositis
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Carmelo Gurnari, Claudiu V. Cotta, Marcin Kalinowski, Gabrielle Yeaney, and Jaroslaw P. Maciejewski
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Pathology ,medicine.medical_specialty ,business.industry ,Biochemistry (medical) ,Clinical Biochemistry ,Hematology ,General Medicine ,medicine.disease ,Settore MED/15 ,T-cell large granular lymphocytic leukemia ,disease associations ,T-Cell Large Granular Lymphocytic Leukemia ,autoimmune complications ,medicine ,Inclusion body myositis ,business - Published
- 2022
3. Very rare Burkitt lymphoma with plasmacytoid differentiation, initial presentation as a CNS tumor, and poor prognosis
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Claudiu V. Cotta, Genevieve M. Crane, Heesun J. Rogers, and Lanisha D Fuller
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Pathology ,medicine.medical_specialty ,Poor prognosis ,business.industry ,Biochemistry (medical) ,Clinical Biochemistry ,Hematology ,General Medicine ,medicine.disease ,Prognosis ,Burkitt Lymphoma ,Lymphoma ,Central Nervous System Neoplasms ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,CNS TUMORS ,Presentation (obstetrics) ,business - Published
- 2021
4. The assembly competence domain is essential for inv(16)-associated acute myeloid leukemia
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Dongquan Chen, C. S. Swindle, Christopher A. Klug, Heidi J. Nick, Scott W. Hiebert, Hyung-Gyoon Kim, S. Purohit-Ghelani, A. D. Friedman, Larry Gartland, Rose M. Ko, Vishnu Reddy, J. LeGrand, Robert A. Oster, and Claudiu V. Cotta
- Subjects
Male ,0301 basic medicine ,Cancer Research ,inv(16) ,assembly competence domain ,acute myeloid leukemia ,Biology ,Core binding factor ,Bioinformatics ,Article ,Domain (software engineering) ,Competence (law) ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,leukemia-initiating cell ,Animals ,Humans ,core-binding factor ,Core Binding Factors ,Myeloid leukemia ,Hematology ,hematopoiesis ,DNA-Binding Proteins ,Mice, Inbred C57BL ,Leukemia, Myeloid, Acute ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Chromosome Inversion ,Core Binding Factor Alpha 2 Subunit ,Cancer research ,Chromosomes, Human, Pair 16 ,Transcription Factors - Published
- 2017
5. Green inclusions in neutrophils—a case report and review of literature
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Alan E. Lichtin, Annette Abraham, and Claudiu V. Cotta
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Liver injury ,030213 general clinical medicine ,medicine.medical_specialty ,Pathology ,Histology ,Hematology ,Critically ill ,business.industry ,Mortality rate ,medicine.disease ,Pathophysiology ,Pathology and Forensic Medicine ,Transplantation ,03 medical and health sciences ,Tuberous sclerosis ,Pneumonia ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,business - Abstract
Green refractile inclusions in neutrophils are a very rare peripheral smear finding with few reported cases in literature. They were thought to be a marker of impending death with a very high mortality rate in the immediate hospitalization period. They were often seen in critically ill patients and often related to liver injury. Clinical and pathophysiologic characterizations of these inclusions are limited due to the rarity of this finding. We describe the case of a 42-year-old woman with tuberous sclerosis and recent renal transplantation who was critically ill due to pneumonia and had elevation of liver enzymes. She was found to have green refractile inclusions on peripheral blood smear on the third day of hospitalization. The patient improved rapidly with treatment and was discharged in 5 days. It appears that prognostic value of these inclusion bodies is doubtful. We also highlight the need to conduct further studies to clarify the link between hepatic injury and the presence of these inclusions.
- Published
- 2017
6. Leukemogenic nucleophosmin mutation disrupts the transcription factor hub that regulates granulomonocytic fates
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Hetty E. Carraway, Tomas Radivoyevitch, Francis Enane, Quteba Ebrahem, Bartlomiej P Przychodzen, Bo T. Porse, Yogen Saunthararajah, Ramesh Balusu, Maria Paola Martelli, Christian Argueta, Jaroslaw P. Maciejewski, David N. Wald, Zhenbo Hu, Nicolas Rapin, Claudiu V. Cotta, Yosef Landesman, Reda Z. Mahfouz, Babal K. Jha, Brunangelo Falini, Xiaorong Gu, and Metis Hasipek
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0301 basic medicine ,THP-1 Cells ,Transport ,Biology ,Monocytes ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,hemic and lymphatic diseases ,CEBPA ,Leukemias ,Animals ,Humans ,Nuclear export signal ,Transcription factor ,Nucleophosmin ,SPI1 ,Nuclear Proteins ,Myeloid leukemia ,General Medicine ,Hematology ,Neoplasm Proteins ,Cell biology ,Leukemia, Myeloid, Acute ,030104 developmental biology ,RUNX1 ,chemistry ,Oncology ,Epigenetics ,Mutation ,Heterografts ,Corepressor ,Neoplasm Transplantation ,Granulocytes ,Transcription Factors ,Research Article - Abstract
Nucleophosmin (NPM1) is among the most frequently mutated genes in acute myeloid leukemia (AML). It is not known, however, how the resulting oncoprotein mutant NPM1 is leukemogenic. To reveal the cellular machinery in which NPM1 participates in myeloid cells, we analyzed the endogenous NPM1 protein interactome by mass spectrometry and discovered abundant amounts of the master transcription factor driver of monocyte lineage differentiation PU.1 (also known as SPI1). Mutant NPM1, which aberrantly accumulates in cytoplasm, dislocated PU.1 into cytoplasm with it. CEBPA and RUNX1, the master transcription factors that collaborate with PU.1 to activate granulomonocytic lineage fates, remained nuclear; but without PU.1, their coregulator interactions were toggled from coactivators to corepressors, repressing instead of activating more than 500 granulocyte and monocyte terminal differentiation genes. An inhibitor of nuclear export, selinexor, by locking mutant NPM1/PU.1 in the nucleus, activated terminal monocytic fates. Direct depletion of the corepressor DNA methyltransferase 1 (DNMT1) from the CEBPA/RUNX1 protein interactome using the clinical drug decitabine activated terminal granulocytic fates. Together, these noncytotoxic treatments extended survival by more than 160 days versus vehicle in a patient-derived xenotransplant model of NPM1/FLT3-mutated AML. In sum, mutant NPM1 represses monocyte and granulocyte terminal differentiation by disrupting PU.1/CEBPA/RUNX1 collaboration, a transforming action that can be reversed by pharmacodynamically directed dosing of clinical small molecules.
- Published
- 2018
7. Favorable outcome of plasmablastic lymphoma expressing both immunoglobulin light chains arising in an immunocompetent man
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Claudiu V. Cotta and Hien K. Duong
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education.field_of_study ,Vincristine ,medicine.medical_specialty ,Pathology ,Histology ,Hematology ,business.industry ,Population ,Plasma cell neoplasm ,medicine.disease ,medicine.disease_cause ,Immunoglobulin light chain ,Epstein–Barr virus ,Pathology and Forensic Medicine ,Internal medicine ,medicine ,Rituximab ,education ,business ,Plasmablastic lymphoma ,medicine.drug - Abstract
This case illustrates the diagnostic and therapeutic challenges posed by neoplasms with plasmablastic features. Even though differentiating between plasmablastic lymphoma (PL) and plasma cell neoplasms can be difficult and somewhat arbitrary, the implications for the therapeutic regimen are significant. In this case, the lesion was identified in the nasal cavity of a previously healthy 37-year-old man, HIV negative. While the neoplasm had all the features of PL, including positivity for Epstein–Barr virus, it also showed sheets of monotypic kappa cells alternating with sheets of monotypic lambda cells. Molecular studies showed a population with clonally rearranged IGH and peaks corresponding to IGK VJ and IGK VKdel. The patient was treated with 3 cycles of rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone, with excellent results. The patient is free of disease more than 20 months later. In the absence of randomized trials investigating the effectiveness of therapeutic protocols for PL, currently aggressive regimens are recommended. This case shows that at least in a subset of the patients with PL, a less aggressive approach may be considered. It is also the first case of PL expressing both light chains.
- Published
- 2012
8. Transient abnormal myelopoiesis of a newborn not associated with chromosome 21 abnormalities orGATA1mutations
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Claudiu V. Cotta, Aron Flagg, Shashirekha Shetty, Charis Eng, Megan O. Nakashima, and Michael Chicka
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Down syndrome ,business.industry ,Myeloid leukemia ,GATA1 ,Spontaneous remission ,Hematology ,medicine.disease ,Germline ,Leukemia ,stomatognathic system ,Oncology ,hemic and lymphatic diseases ,Pediatrics, Perinatology and Child Health ,Immunology ,medicine ,skin and connective tissue diseases ,Trisomy ,Chromosome 21 ,business ,hormones, hormone substitutes, and hormone antagonists - Abstract
Transient abnormal myelopoiesis (TAM) is a disorder of Down syndrome newborns characterized by megakaryocytic blasts indistinguishable from acute myeloid leukemia (AML), which undergoes spontaneous remission. Acquired GATA1 mutations are present in blasts of both TAM and the subsequent AML which sometimes develops. We present a unique case of a newborn with leukemic megakaryoblasts indistinguishable from those of TAM who had neither extra material from chromosome 21 in the germline or blasts, nor evidence of GATA1 mutations. These findings suggest there are other genetic abnormalities that can lead to TAM besides GATA1 mutation in the setting of trisomy 21. Pediatr Blood Cancer 2015;62:353-355. © 2014 Wiley Periodicals, Inc.
- Published
- 2014
9. A Phase 1 study of imatinib mesylate in combination with cytarabine and daunorubicin for c-kit positive relapsed acute myeloid leukemia
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Claudiu V. Cotta, Kathleen Lim, Jennifer Bates, Matt Kalaycio, Mikkael A. Sekeres, Courtney Price, Barbara Tripp, Ronald Sobecks, Edward A. Copelan, Elysa Noon, Ramon V. Tiu, Anjali S. Advani, A. Salvado, Matthew T. Howard, Yogen Saunthararajah, Eric D. Hsi, Merrill J. Egorin, Mary Lynn Rush, Jaroslaw P. Maciejewski, and Tao Jin
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Adult ,Male ,Cancer Research ,Myeloid ,Maximum Tolerated Dose ,Daunorubicin ,Piperazines ,Recurrence ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,STAT5 Transcription Factor ,medicine ,Humans ,Phosphorylation ,Receptor ,neoplasms ,Aged ,business.industry ,Cytarabine ,Myeloid leukemia ,Hematology ,Middle Aged ,medicine.disease ,Leukemia, Myeloid, Acute ,Proto-Oncogene Proteins c-kit ,Leukemia ,Pyrimidines ,Imatinib mesylate ,medicine.anatomical_structure ,Oncology ,Benzamides ,Toxicity ,Imatinib Mesylate ,Cancer research ,Female ,business ,medicine.drug - Abstract
The c-kit receptor is expressed in 95% of relapsed acute myeloid leukemias (AMLs) and mediates leukemic proliferation. We conducted a Phase 1 study of the c-kit inhibitor, imatinib mesylate (IM), in combination with cytarabine and daunorubicin (7+3) in c-kit+ relapsed AML. IM was dose escalated using a 3 by 3 design. Phosphorylated STAT5 was absent to minimally present in residual blasts on day 14 bone marrows. The maximum tolerated dose of IM was 300 mg. The dose-limiting toxicity was Grade 3-4 hepatic toxicity. The CR/CRp rate was 57%. Cytotoxic therapy that includes IM for relapsed AML is well-tolerated and effective.
- Published
- 2010
10. Concomitant conjunctival mucosa-associated lymphoid tissue lymphoma and small lymphocytic lymphoma associated with immunoglobulin M macroglobulinemia successfully treated with intensity modulated radiation therapy
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John Sweetenham, Ramon V. Tiu, Arun D. Singh, Claudiu V. Cotta, and Juliann Workman
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Cancer Research ,Pathology ,medicine.medical_specialty ,biology ,business.industry ,Chronic lymphocytic leukemia ,Mucosa-Associated Lymphoid Tissue Lymphoma ,Macroglobulinemia ,Hematology ,medicine.disease ,Lymphocytic lymphoma ,Lymphoma ,Lymphatic system ,Oncology ,immune system diseases ,Immunoglobulin M ,hemic and lymphatic diseases ,Concomitant ,Immunology ,medicine ,biology.protein ,business - Abstract
Small lymphocytic lymphoma (SLL)/chronic lymphocytic leukemia (CLL) and mucosa-associated lymphoid tissue (MALT) lymphoma are lymphoid malignancies that usually behave in an indolent manner. Walden...
- Published
- 2010
11. The Mechanisms By Which Mutant-NPM1 Uncouples Differentiation from Proliferation Are Reversed By Several Drugs, Enabling Rational Multi-Component Non-Cytotoxic Differentiation Therapy
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Tomas Radivoyevitch, Ramesh Balusu, Babal K. Jha, Brunangelo Falini, Hetty E. Carraway, Maria Paola Martelli, Metis Hasipek, Reda Z. Mahfouz, Bartlomiej P Przychodzen, Claudiu V. Cotta, Zhenbo Hu, Nicolas Rapin, Yogenthiran Saunthararajah, Jaroslaw P. Maciejewski, Yosef Landesman, David N. Wald, Quteba Ebrahem, Xiaorong Gu, and Francis Enane
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Myeloid ,Chemistry ,Monocyte ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Biochemistry ,Molecular biology ,Haematopoiesis ,chemistry.chemical_compound ,medicine.anatomical_structure ,RUNX1 ,Differentiation therapy ,CEBPA ,medicine ,Cytotoxic T cell - Abstract
NPM1 is the most frequently mutated gene in acute myeloid leukemia (AML). Unfortunately, there are no 'precision' or rational treatments for this subtype of AML.To elucidate molecular mechanisms of pathogenesis, we performed the first comprehensive, unbiased analysis of the endogenous NPM1 protein-interactome using mass-spectrometry (LC-MS/MS). This approach identified abundant amounts of the master transcription factor driver of monocyte lineage-differentiation PU.1 (SPI1). The NPM1/PU.1 interaction causes PU.1 functional deficiency when NPM1 is mutated, because mutant-NPM1 dislocates PU.1 into the cytoplasm with it.This was confirmed using six different methods: (i) Immunoprecipitation (IP)-LC-MS/MS from nuclear and cytoplasmic fractions of wildtype (wt) and NPM1 -mutated AML cell lines (n=2); (ii) IP-Western blot (WB) from nuclear/cytoplasmic fractions of NPM1 -mutated/wt AML cell lines (n=2); (iii) WB of nuclear/cytoplasmic fractions of NPM1 -mutated/wt AML cell lines (n=5); (iv) immunofluorescence microscopy (IF) of NPM1 -mutated/wt AML cell lines (n=5); (v) IF of NPM1 -mutated/wt primary AML cells (n=6); and (vi) cotransfection of HEK293 cells to express PU.1 + mutant vs wt-NPM1 followed by IF. Re-introduction of Pu.1 into the nucleus of Pu.1-null myeloid precursors which are differentiation-arrested and exponentially proliferating repressed key myeloid precursor genes (e.g., Hoxa9) and triggered terminal monocytic differentiation. Even though primary AML cells (n=900) express the PU.1/RUNX1/CEBPA monocyte differentiation-driving master transcription factor circuit at levels comparable to or exceeding that in normal monocytes, the expression of ~300 monocyte terminal-differentiation genes was suppressed. Importantly, the genes affected are strongly positively correlated (avg. rho 0.7) with PU.1 expression in normal hematopoiesis, consistent with functional disruption of PU.1 in AML. To translate these observations into a treatment option for NPM1 -mutated AMLs, we were guided by additional observations. First, the NPM1/PU.1 protein complex is exported by the nuclear export protein XPO1. XPO1-mediated nuclear export is inhibited by the small molecule selinexor. We found that sub-cytotoxic /low nanomolar concentrations of selinexor locked mutant-NPM1/PU.1 in the nucleus, releasing terminal monocytic differentiation of NPM1 -mutated AML cells both in vitro and in vivo . Briefly, NSG mice were xenotransplanted with NPM1 / FLT3 -mutated primary AML cells and observed until AML engraftment (≥20%) was confirmed. Selinexor was then administered by oral gavage at 2 mg/kg 4X/week (Fig1A), which is 10-fold lower than the usual in vivo cytotoxic dose (15-20 mg/kg) - low doses are well-tolerated and sufficient to promote non-cytotoxic differentiation of AML cells. After 50 days of treatment, bone marrow (Fig1B) and spleen (Fig1C) AML burden was significantly lower in selinexor vs vehicle treated mice. In addition, selinexor treated mice preserved murine hematopoiesis (Fig1D) and IF confirmed the partial nuclear restoration of PU.1 (Fig1E). Terminal monocytic differentiation of AML cells was evident by Giemsa-stained morphology (Fig1F) and flow cytometry (Fig1G). RUNX1 and CEBPA remain in NPM1 -mutated AML cell nuclei at high levels - PU.1 usually cooperates with these master transcription factor partners to exchange corepressors for coactivators and activate differentiation genes. Accordingly, IP-LC-MS/MS of endogenous nuclear CEBPA demonstrated enrichment for corepressors. Depletion of one of these corepressors, DNMT1, using non-cytotoxic concentrations of decitabine or 5-azacytidine (clinical DNMT1-depletors), also induced terminal-differentiation. Moreover, the granulocytic direction of differentiation naturally downregulated NPM1, an event inherent to CEBPA-driven granulocytic (but not monocytic) differentiation. This approach readily induced terminal-differentiation in NPM1 -mutated AML cells selected over 52 weeks of culture for resistance to selinexor, shown by exponential growth in selinexor 20 nM. The mechanisms by which mutant-NPM1 creates leukemic self-replication (proliferation uncoupled from differentiation) are thus reversed by non-cytotoxic molecular targeted clinical drugs. We are evaluating the combination of selinexor with non-cytotoxic DNMT1-depletion in vivo and clinical trials are planned. Disclosures Landesman: Karyopharm Therapeutics: Employment.
- Published
- 2017
12. Successful treatment of Hodgkin lymphoma and acute leukemia
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Claudiu V. Cotta, Galena Khan, Brad Pohlman, John Sweetenham, and Robert Wesolowski
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Cancer Research ,medicine.medical_specialty ,Lymphatic metastasis ,Acute leukemia ,Myeloid ,medicine.diagnostic_test ,business.industry ,Hematology ,medicine.disease ,Supraclavicular lymphadenopathy ,Gastroenterology ,Leukemia ,Remission induction ,medicine.anatomical_structure ,Oncology ,Internal medicine ,Biopsy ,medicine ,Hodgkin lymphoma ,business - Abstract
A previously healthy 31-year-old man was seen at our institution for evaluation of severe fatigue, night sweats, and supraclavicular lymphadenopathy. About 9 months earlier, he experienced symptoms...
- Published
- 2009
13. The Mechanism By Which Mutant Nucleophosmin (NPM1) Creates Leukemic Self-Renewal Is Readily Reversed
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Maria Paola Martelli, Zhenbo Hu, Claudiu V. Cotta, Reda Z. Mahfouz, Jaroslaw P. Maciejewski, Xiaorong Gu, Brunangelo Falini, Quteba Ebrahem, Yogenthiran Saunthararajah, Tomas Radivoyevitch, Bartlomiej P Przychodzen, Michael J. Clemente, David N. Wald, Francis Enane, Ramesh Balusu, and Yosef Landesman
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Myeloid ,Immunology ,Cell ,Cell Biology ,Hematology ,Cell cycle ,Biology ,Biochemistry ,Cell biology ,03 medical and health sciences ,Haematopoiesis ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Monocyte differentiation ,CEBPA ,medicine ,Stem cell ,Transcription factor ,030215 immunology - Abstract
Acute myeloid leukemia (AML) is self-renewal by immature myeloid precursors that fail to differentiate. An influential 'leukemia stem cell' model thus proposes that leukemogenic proteins augment or introduce a stem cell-like self-renewal program into cells, e.g., by upregulating signaling or transcription factors (TF) emblematic of stem cells (e.g., HOX). We investigated how the most recurrently mutated protein in AML, mutant nucleophosmin (mNPM1), causes leukemic cell expansion. The results challenge this model, but most importantly, open the door to rational targeted therapy for mNPM1 AML. One way of examining for stem cell programs in AML cells is to look at expression patterns of master TF that regulate expression of hundreds of genes and dictate cell fates. Of these select TF, the master TF that create hematopoietic stem cells (HLF etc.) are minimally or not expressed. Instead, there are very high levels of the master TF that drive monocyte and granulocyte lineage fates, PU.1 (SPI1) and CEBPA. Clearly, however, the lineage-programs intended by PU.1/CEBPA are inefficiently executed if at all - mNPM1 AML patient bone marrows had 85-97% cells with a granulocyte-monocyte progenitor phenotype, accumulated at the expense of downstream mature cells (Quek et al, JEM 2016). This aggregation at a lineage-committed, intermediate, naturally proliferative level of the hematopoietic hierarchy suggests an alternative model - instead of introducing a poorly-defined stem cell self-renewal program, mutant proteins disable differentiation programs which usually quench MYC-driven proliferation intrinsic to lineage-progenitors. To better understand how mNPM1 interacts with cellular machinery, we used mass-spectrometry to comprehensively document the protein interactions of endogenous NPM1 in AML cell nuclear and cytoplasmic fractions, the first analysis of this kind. Notably, the NPM1 protein interactome was enriched for PU.1. Critically, wild-type (wt) NPM1/PU.1 was in the nucleus of wtNPM1 AML cells, but mNPM1/PU.1 was in the cytoplasm of mNPM1 AML cells. This was evident clearly also by Western blot of cell fractions and by IF microscopy of primary AML cells and cell lines. Is cytoplasmic dis-location of PU.1 sufficient to explain persistent hematopoietic precursor proliferation? We used murine Pu.1 knock-out hematopoietic precursors transduced to express Pu.1 fused with the estrogen receptor (Pu.1-ER) to answer this question - Pu.1 relocation from the cytoplasm to the nucleus by tamoxifen triggered monocytic differentiation that terminated proliferation. Moreover, Pu.1-ER cells, like mNPM1 AML cells, highly express Hox genes, rapidly suppressed upon Pu.1 relocation to the nucleus. Thus, Pu.1 dominantly controls Hox and proliferation, as befitting of a master TF, and persistent HOX expression, like persistent progenitor proliferation, can be caused by Pu.1 loss-of-function. Protein macromolecules like NPM1 require transport factors to exit (exportins) the nucleus. A specific exportin, XPO1, was the major exportin found in the NPM1 interactome. XPO1 interactions with transported cargo can be inhibited by the small molecule drug KPT330. KPT330 10-20 nM rapidly re-located mNPM1 and PU.1 to the nucleus, downregulated MYC, upregulated p27/CDKN1B, upregulated monocyte but not granulocyte differentiation markers, induced morphologic changes of monocyte differentiation, and terminated proliferation of mNPM1 AML cells. The same low nanomolar treatment did not induce differentiation of wtNPM1 AML cells (THP1). Moreover, these KPT330 levels are not toxic to normal hematopoiesis (also shown by others). Thus, rather than gain-of-function of elusive stem cell-like self-renewal, the most frequently mutated protein in AML creates self-renewal by disabling a differentiation program that quenches intrinsic MYC-driven proliferation of lineage-progenitors. These observations are a mechanistic rationale to select refractory/relapsed mNPM1 AML patients for treatment with low well-tolerated doses of KPT330, with a defined molecular pharmacodynamic objective of returning PU.1 to the nucleus, to produce cell cycle exits by differentiation rather than p53-mediated apoptosis (to address chemotherapy resistance), to spare precious normal HSC (good therapeutic index), and directly reverse the basis for leukemic self-renewal (proliferation without differentiation). Figure. Figure. Disclosures Landesman: Karyopharm Therapeutics Inc: Employment, Other: stockholder. Saunthararajah:EpiDestiny: Consultancy, Other: patents around decitabine and tetrahydrouridine.
- Published
- 2016
14. Gelatinous transformation
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Claudiu V. Cotta
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Male ,Lymphoma, B-Cell ,Immunology ,Ascites ,Anemia ,Cell Biology ,Hematology ,Biochemistry ,Bone Marrow ,Edema ,Humans ,Hyaluronic Acid ,Extracellular Space ,Aged - Published
- 2012
15. Long-Term Follow-up Results: A Phase 2 Trial of Imatinib Mesylate As Maintenance Therapy for Patients with Newly Diagnosed c-Kit Positive Acute Myeloid Leukemia (AML)
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Laura Bailey, Arati V. Rao, Ronald Sobecks, Elizabeth A. Griffiths, Bethany Foster, Claudiu V. Cotta, Francis Ali-Osman, Brenda W. Cooper, Mikkael A. Sekeres, Paul Elson, Anjali S. Advani, William Tse, Xuefei Jia, Jaime Fensterl, David A. Rizzieri, Eunice S. Wang, Donna Adams, Jino Park, Matt Kalaycio, Jennifer S. Carew, Basel Rouphail, Mary Lynn Rush, and Jaroslaw P. Maciejewski
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Oncology ,medicine.medical_specialty ,Anthracycline ,business.industry ,Immunology ,Imatinib ,Cell Biology ,Hematology ,Biochemistry ,Imatinib mesylate ,Maintenance therapy ,Refractory ,Internal medicine ,Cytarabine ,Medicine ,business ,Dose Reduced ,Etoposide ,medicine.drug - Abstract
The c-kit (CD117) receptor is expressed on > 10% blasts in 64% of de novo AMLs and mediates proliferation and anti-apoptotic effects. High c-kit levels [defined as mean fluorescent intensity (MFI) > 20] correlate with a shorter time to relapse and decreased overall survival (OS). Imatinib mesylate (IM), a c-kit inhibitor, has activity against relapsed/ refractory AML. The primary objective of this study was to determine whether adding maintenance IM for 1 yr after completion of standard induction (IT) and post-remission therapy (PRT) in pts with newly diagnosed c-kit + AML improves progression-free survival (PFS) compared to historical controls. We previously presented our toxicity and correlative data at ASH 2012 (Abstract 3597). Here, we present our long term follow-up results. Methods: Pts were treated at Cleveland Clinic, Duke, Roswell Park, and University Hospitals of Cleveland from 2008 to 2012. IM was supplied by Novartis. Eligibility criteria: pts age ≥ 18 yrs, AML in first complete remission (CR1), ≥ 20% c-kit+ blasts at diagnosis (dx), ECOG performance status 0-2. Cytogenetics (CG) were classified per CALGB 8461. Pts must have received IT (7+3 [continuous infusion cytarabine and an anthracycline] or ADE [cytarabine, daunorubicin, etoposide]) and PRT (≥ 1 course for pts ≥ 60 yrs; ≥ 2 courses for pts < 60 yrs). CR was confirmed by bone marrow analysis prior to study enrollment. MDR expression was analyzed by IHC on diagnostic samples (n=19); AF1q gene expression was analyzed by RT-PCR on RNA from available diagnostic pt samples (n=9). C-kit MFI was calculated as the mean channel number (MCN) of the blasts/ MCN auto fluorescence using a CD45/orthogonal light scatter gate to isolate blasts and lymphocytes. All pts received IM 600 mg/day for 12 months (mos) unless they experienced toxicity or disease progression. Dose modifications were made for Grade 2-4 non-hematologic toxicity and Grades 3-4 neutropenia and thrombocytopenia. PFS was measured from the CR date to the time of relapse or death. Primary endpoints: Based on historical data from the Cleveland Clinic and SWOG, the median PFS for all AML pts undergoing IT < 60 yrs of age is 13 mos and for pts ≥ 60 yrs of age is 8 mos. The goal of this study was to see a 30% improvement in PFS at these time points in the respective age groups (i.e. 65% PFS at 13 mos for pts < 60 yrs; 65% PFS at 8 mos for pts ≥ 60 yrs). Results: Of 32 pts enrolled, the median age was 54 yrs (range 19-81), median WBC at dx 22.13 K/ uL (1.55-98.44), median peripheral blood blasts at dx 23.6% (range 0-85), and 44% were male. CG risk included: 16% (5) good, 66% (21) intermediate, 16% (5) poor, 3% (1) miscellaneous. Of the pts with normal CG, 10 were NPM1+, FLT3 ITD negative; and 1 pt was FLT3 ITD+. The median c-kit+ blast % was 79.9, and median c-kit MFI 39.8 (range 6.5-120.1). Median AF1q expression was 9.59 (range 1.83-161.85) (> 9 is considered high and is associated with a poor prognosis; high AF1q is also associated with high c-kit expression). Eight-four percent of pts had moderate or high levels of drug resistance factors (GST1, MDR1, LRP1, and/or MRP1); almost half (47%) had high expression. There was no correlation between MDR and c-kit MFI. Pts received IM for a median of 4.0 mos (range 0.1-12.2) and the median daily dose was 600 mg. Twelve pts (38%) were dose reduced to 400 mg. Forty-five percent of pts experienced Grade 3 reactions possibly related to treatment, with the majority (31%) being myelosuppression. With a median follow-up time of 56.3 mos, the estimated median OS was 51.3 mos and estimated median relapse-free survival (RFS) 18.9 mos. The estimated PFS at 13 mos for pts < 60 yrs of age was 71 ± 10% (p=0.017, compared to the null hypothesis); and the estimated PFS at 8 mos for pts ≥ 60 yrs of age was 64 ± 15% (p=0.166, compared to the null hypothesis). Predictors of worse RFS included: age, WBC at dx, % peripheral blasts at dx, CG risk, and MDR expression. C-kit MFI and Af1q were not associated with RFS or OS. Conclusions: Use of IM maintenance therapy appeared to be associated with improved PFS compared to historical controls in pts < 60 yrs of age. In addition to a high c-kit MFI, these pts had other adverse characteristics (moderate to high levels of MDR. high AF1q). Though previous studies have demonstrated that c-kit MFI > 20.3 was an independent adverse prognostic factor for RFS and OS (median RFS 10.7 months) in AML, use of IM maintenance therapy in this study appeared to mitigate this, supporting further investigation. Disclosures Off Label Use: imatinib in the treatment of AML. Rao:Boehringer-Ingelheim: Other: Advisory Board; amgen: Other: ad board; novartis: Other: ad board. Rizzieri:Teva: Other: ad board, Speakers Bureau; Celgene: Other: ad board, Speakers Bureau. Wang:Immunogen: Research Funding. Griffiths:Alexion Pharmaceuticals: Honoraria; Astex: Research Funding; Celgene: Honoraria. Sekeres:TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees.
- Published
- 2015
16. Pathobiology of mature T-cell lymphomas
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Eric D. Hsi and Claudiu V. Cotta
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Cancer Research ,Pathology ,medicine.medical_specialty ,CD30 ,T-Lymphocytes ,Biology ,Mature T-Cell ,Lymphoma, T-Cell ,World health ,medicine ,Humans ,Leukemia-Lymphoma, Adult T-Cell ,Hematopoietic Neoplasms ,Prolymphocytic leukemia ,Genetic testing ,Mycosis fungoides ,medicine.diagnostic_test ,Lymphoma, T-Cell, Peripheral ,Hematology ,General Medicine ,medicine.disease ,Killer Cells, Natural ,Leukemia, Large Granular Lymphocytic ,stomatognathic diseases ,Leukemia ,Oncology ,Immunoblastic Lymphadenopathy ,Leukemia, Prolymphocytic, T-Cell - Abstract
Mature T- and natural killer (NK)-cell neoplasms are relatively rare forms of leukemia/lymphoma. The diagnosis of these entities is often difficult, necessitating extensive immunophenotypic, molecular, and genetic testing. Despite the accumulating information on the pathobiology of these neoplasms, in many cases the prognosis remains poor. This article presents an updated view of the morphologic, immunophenotypic, genetic, and molecular characteristics of the mature T- and NK-cell neoplasms. For a better understanding of this complex topic, the development of normal T and NK cells is briefly discussed. The presentation of the characteristic features of the neoplasms in the 2008 World Health Organization classification of hematopoietic neoplasms includes advances in the understanding of the pathobiology of each diagnostic category.
- Published
- 2008
17. FLT3-ITD cooperates with inv(16) to promote progression to acute myeloid leukemia
- Author
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Claudiu V. Cotta, Yongliang Huo, Christopher A. Klug, Vishnu Reddy, Hyung-Gyoon Kim, C. Scott Swindle, and Kyoko Kojima
- Subjects
medicine.medical_specialty ,Myeloid ,Oncogene Proteins, Fusion ,Immunology ,Biology ,Biochemistry ,Core Binding Factor beta Subunit ,Mice ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Animals ,Lymphopoiesis ,Myelopoiesis ,Hematology ,Neoplasia ,Myeloid leukemia ,Cell Biology ,Smooth Muscle Myosins ,medicine.disease ,Hematopoietic Stem Cells ,Transplantation ,Survival Rate ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,fms-Like Tyrosine Kinase 3 ,Chromosome Inversion ,Mutation ,Cancer research ,Disease Progression ,Bone marrow - Abstract
The inversion of chromosome 16 in the inv(16)(p13q22) is one of the most frequent cytogenetic abnormalities observed in acute myeloid leukemia (AML). The inv(16) fuses the core binding factor (CBF) beta subunit with the coiled-coil rod domain of smooth muscle myosin heavy chain (SMMHC). Expression of CBFβ-SMMHC in mice does not promote AML in the absence of secondary mutations. Patient samples with the inv(16) also possess mutually exclusive activating mutations in either N-RAS, K-RAS, or the receptor tyrosine kinases, c-KIT and FLT3, in almost 70% of cases. To test whether an activating mutation of FLT3 (FLT3-ITD) would cooperate with CBFβ-SMMHC to promote AML, we coexpressed both mutations in hematopoietic progenitor cells used to reconstitute lethally irradiated mice. Analysis of transplanted animals showed strong selection for CBFβ-SMMHC/FLT3-ITD–expressing cells in bone marrow and peripheral blood. Compared with animals transplanted with only CBFβ-SMMHC–expressing cells, FLT3-ITD further restricted early myeloid differentiation and promoted peripheralization of primitive myeloblasts as early as 2.5 weeks after transplantation. FLT3-ITD also accelerated disease progression in all CBFβ-SMMHC/FLT3-ITD–reconstituted animals, which died of a highly aggressive and transplantable AML within 3 to 5 months. These results indicate that FLT3-activating mutations can cooperate with CBFβ-SMMHC in an animal model of inv(16)-associated AML.
- Published
- 2008
18. Expression of a non–DNA-binding isoform of Helios induces T-cell lymphoma in mice
- Author
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C. Scott Swindle, John T. Bates, Rose M. Ko, Zheng Zhang, Claudiu V. Cotta, and Christopher A. Klug
- Subjects
Gene isoform ,Cellular differentiation ,Immunology ,Mutant ,Gene Expression ,HeliOS ,Thymus Gland ,Biology ,medicine.disease_cause ,Lymphoma, T-Cell ,Biochemistry ,Mice ,medicine ,Animals ,Protein Isoforms ,Transcription factor ,Cells, Cultured ,Cell Proliferation ,Mutation ,Neoplasia ,Cell Differentiation ,Cell Biology ,Hematology ,Molecular biology ,Transplantation ,DNA-Binding Proteins ,Killer Cells, Natural ,Mice, Inbred C57BL ,Thymocyte ,Cell Transformation, Neoplastic ,Transcription Factors - Abstract
Helios is a zinc-finger protein belonging to the Ikaros family of transcriptional regulators. It is expressed, along with Ikaros, throughout early stages of thymocyte development where it quantitatively associates with Ikaros through C-terminal zinc-finger domains that mediate heterodimerization between Ikaros family members. To understand the role of Helios in T-cell development, we used a retroviral vector to express full-length Helios or a Helios isoform that lacked the N-terminal DNA-binding domain in hematopoietic progenitor cells of reconstituted mice. Constitutive expression of full-length Helios resulted in an inhibition of T-cell development at the double-negative stage within the thymus. Although expression of the DNA-binding mutant of Helios did not contribute to developmental abnormalities at early times after transplantation, 60% of animals that expressed the Helios DNA-binding mutant developed an aggressive and transplantable T-cell lymphoma 4 to 10 months after transplantation. These results demonstrate a vital function for Helios in maintaining normal homeostasis of developing T cells and formally show that non–DNA-binding isoforms of Helios are lymphomagenic if aberrantly expressed within the T-cell lineage.
- Published
- 2007
19. Bone Marrow Core Biopsy Adequacy and Variability in the United Stated and Canada: A Multicenter Retrospective Study
- Author
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LoAnn Peterson, Robert E. Hutchison, Elizabeth L. Courville, Mihai Merzianu, Fernandez Garcia, Sinisa Ivelja, Prabhjot Kaur, Claudiu V. Cotta, Vishnu Vb Reddy, Ridas Juskevicius, Vishala Neppalli, Sharon Barouk, Russell K. Brynes, Michael R. Lewis, John Lazarchick, Gratian Salaru, Ashley V Sedelmeyer, Vivian Arguello, David D. Grier, Shanxing Zhang, Hina Naushad, John T Grantham, James E. Coad, Alana DiPonio, Horatiu Olteanu, Ling Zhang, Manjula Balasubramanian, Rodney R. Miles, Robert W. McKenna, Kedar V. Inamdar, Jie Xu, Elisa F Brega, Neerja Vajpayee, Kieran Sultan, Adrienne Groman, George Deeb, Richie Carpenter, Julie Teruya-Feldstein, Guang Fan, Matthew B. Thomsen, Daniela Hoehn, Sindhu Cherian, Attilio Orazi, Richard T. Cheney, David R. Czuchlewski, Jerome B. Myers, Jeffrey A. Vos, Guilherme Brandao, Gregory E. Wilding, Michel R. Nasr, Ramila Amre, Le Aye, and Valentin G. Robu
- Subjects
medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Immunology ,Retrospective cohort study ,Cell Biology ,Hematology ,Biochemistry ,Surgery ,Bone marrow examination ,medicine.anatomical_structure ,Hematologic disorders ,Statistical significance ,Cohort ,medicine ,Sampling (medicine) ,Bone marrow ,Nuclear medicine ,business ,Core biopsy - Abstract
BACKGROUND Bone marrow examination is essential in diagnosis, staging and monitoring of various hematologic disorders. The aspirate smears and core biopsy are complementary samples; current clinical benchmarks recommend an optimal core sample length of at least 15-20 mm. We assessed the core length in 2 cross-sectional cohorts from 2001 and 2011 in 32 academic medical centers from the US and Canada, the first such study to date. METHODS After IRB approval, participants collected data from pathology reports (including the preprocessing length) and measured aggregate postprocessing and evaluable marrow length using a uniform validated methodology on 100 consecutive marrow samples in 2001 and 2011 at each institution. Deidentified data was centralized at Roswell Park Cancer Institute (RPCI) and centers were anonymized. A total of 6374 samples were accepted for statistical analysis, performed using SAS (v. 9.4 or higher; SAS Institute, Cary, NC) at RPCI. Relationship between core length and NCCN status, geographic location, gender, age, and staging was assessed using the PROC MIXED and PROC GLIMMIX procedure using a random center effect and a nominal significance level of 0.05. RESULTS The study cohort included 56% men and 44% women, mean age 51 (range, 1-102) years, 88% adults (³18) and 12% children ( A core biopsy was obtained in 90% of 2001 and in 95% of 2011 samples. Most cores were unilateral (85%); bilateral sampling decreased from 10% to 4% between 2001 and 2011. An aspirate specimen was received in the pathology department in 86% of the cases; however, a clot section was prepared in only 56% of the cases. Preprocessing core length (PreCL; n=3141) documentation in pathology reports was missing in 9 centers for both years; in 3 centers it was available only for one year; its mean (standard deviation) was 16.9 (9.9) mm, decreasing from 2001 to 2011 [17.7 (11.9) to 16.2 (8); p=0.002]. Postprocessing core length (PostCL; n=5742) mean (SD) was 14.2 (8.5) mm, significantly shorter in women than in men (p Evaluable marrow space length (EML; n=5617) mean (SD) was 10.7 (7.5) mm and decreased from 2001 to 2011 [10.9 (8.5) to 10.6 (6.6); p=0.002]. Ninety-one samples (1.6%) with measureable PostCL were entirely devoid of evaluable marrow. PostCL was 15% shorter than PreCL. The EML measured 24% less than the PostCL and 33% less than the PreCL. Lymphoma staging samples (n=1222) were obtained from adults (96%) and children (4%); of these, only 45% and 28% reached the PostCL of 15 mm and 20 mm, respectively. Lymphoma involvement rate was 16%, 25%, 32%, 30%, and 23% when PostCL was There was no significant difference of PostCL mean based on geographic region or NCCN status. PostCL mean ranged from 8.8 to 29.6 mm and its median was ³15 mm in only 12 of 23, 9 of 32, and 2 of 32 centers for PreCL, PostCL, and EML, respectively (Fig 3). When compared to current benchmarks, only 53%, 38%, and 22% of all samples were ³15 mm and only 30%, 19%, and 10% were ³20 mm for PreCL, PostCL, and EML, respectively. CONCLUSIONS Current benchmarks for bone marrow core biopsy adequacy are met in only a minority of cases. Samples from women were shorter than from men. Bilateral sampling decreased and PreCL and EML diminished significantly between 2001 and 2011, while PostCL showed only minimal decrease. This discrepancy may be due to technical differences. Although staging cores were longer than non-staging ones, most did not meet the benchmarks. The wide variability among different centers suggests significant institutional differences and lack of standardization in bone marrow sampling. Over a third of all centers did not record preprocessing length, an important parameter which may guide operator assessment of adequacy at the bedside. PostCL and/or EML can be measured by the pathologist and integrated in the report to document adequacy. In staging samples, a minimal marrow space sampling should be required to avoid understaging. Consensus definition of an inadequate core biopsy is currently lacking but would be desirable for uniform pathology reporting, clinical protocols and management. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.
- Published
- 2014
20. A Novel in Vitro Three Organ System Assay Identifies a Small Molecule Ubiquitin Analog with in Vivo Activity Against Myeloma
- Author
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Dale Grabowski, Claudiu V. Cotta, James G. Phillips, Frederic J. Reu, Daniel J. Lindner, Yvonne Parker, Sergei Vatolin, and Shravya Govindgari
- Subjects
Stromal cell ,Bortezomib ,Ubiquitin-activating enzyme ,Immunology ,Cell Biology ,Hematology ,UBA1 ,Biology ,Biochemistry ,Molecular biology ,Protein ubiquitination ,medicine.anatomical_structure ,Ubiquitin ,Proteasome inhibitor ,medicine ,biology.protein ,Bone marrow ,medicine.drug - Abstract
Taking a mechanistically unbiased approach to the discovery of new myeloma drugs we developed a three organ system assay that selected anti-myeloma compounds from a primary 30,000 small molecule ATP-based screen in one sandwich setup for tolerability by normal bone marrow, stability towards liver enzymes, and activity in the context of cell barriers, bone marrow stromal support, and short, kidney-clearance-like exposure (fig.1). The most promising compound (CCF642) emerging from this test had IC50s around 500 nM in all 8 MM cell lines tested including a proteasome inhibitor refractory line while the IC50 was not reached in 5 healthy bone marrow samples at doses up to 6750 nM. Similar sensitivity as in MM was seen in 7 lymphoma cell lines. Investigation of its mechanism of action revealed that CCF642 immediately stimulates protein ubiquitination which is followed by degradation of major myeloma survival factors (c-MYC, IRF4, NF-κB) and apoptosis, while normal bone marrow cells increase ubiquitination to a much lesser degree and only transiently without undergoing cell death. Experiments with an active biotinylated analog showed that it preferentially enters myeloma cells with cytoplasmic accumulation and over 10-fold lower entry into normal bone marrow. Immunoblots revealed that it becomes covalently attached to proteins in a time- and distribution pattern that parallels ubiquitination responses. In vitro, it bound to ubiquitin activating enzyme UBA1 at the active site cysteine in a similarly stable and reversible way as ubiquitin. Selective alkylation of cysteine sulfhydryl groups inhibited binding of biotinylated CCF642 to UBA1, while addition of ATP and ubiquitin led to its dissociation from UBA1. CCF642 may therefore at least in part act as a small molecule ubiquitin analog. Accordingly CCF642 binding to target proteins of UBA1 containing HeLa fraction II was increased by addition of ATP and blocked in the presence of EDTA. Injected twice a week IP at 30mg/kg it suppressed systemically engrafted luciferase expressing 5TGM1 mouse myeloma cells in syngeneic mice comparable to bortezomib given at the MTD for this mouse strain (0.5mg/kg SC twice a week) with equal prolongation of survival. Results support use of our sandwich assay to select myeloma drug candidates for in vivo testing and reveal a new UBA1 interacting small molecule ubiquitination enhancer with promise for clinical translation. Figure 1: Sandwich Three Organ System Assay Figure 1:. Sandwich Three Organ System Assay Disclosures No relevant conflicts of interest to declare.
- Published
- 2014
21. The ETS family transcription factor PU.1 is necessary for the maintenance of fetal liver hematopoietic stem cells
- Author
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Cristina G. de Guzman, Hyung-Gyoon Kim, Larry Gartland, Edward W. Scott, C. Scott Swindle, Christopher A. Klug, and Claudiu V. Cotta
- Subjects
Liver cytology ,Immunology ,CD34 ,Biology ,Biochemistry ,Mice ,Fetus ,Proto-Oncogene Proteins ,medicine ,Animals ,Progenitor cell ,Crosses, Genetic ,Progenitor ,Mice, Knockout ,Hematopoietic stem cell ,Cell Biology ,Hematology ,Flow Cytometry ,Hematopoietic Stem Cells ,Embryonic stem cell ,Cell biology ,Mice, Inbred C57BL ,Haematopoiesis ,medicine.anatomical_structure ,Liver ,Trans-Activators ,Stem cell ,Transcription Factors - Abstract
PU.1 is a member of the ETS family of transcription factors and is required for the development of multiple hematopoietic lineages. PU.1-/- mice die from hematopoietic failure at about embryonic day 18.5 (e18.5) and show a complete absence of B cells, mature T cells, and macrophages. This phenotype suggests that PU.1 may function at the level of the hematopoietic stem cell (HSC) or a multilineage progenitor. To investigate the role of PU.1 in the regulation of HSCs, PU.1-/- embryos were analyzed at various stages of embryonic development. The absolute number and frequency of HSCs were determined by flow cytometric analysis of c-Kit+Thy-1.1loLin-Sca-1+ (KTLS) cells. We found that KTLS cells were absent or severely reduced in PU.1-/- fetal liver from e12.5 to e15.5. Progenitor cells with a c-Kit+Lin-AA4.1+ and c-Kit+Lin-CD34+ phenotype were also severely reduced. In addition, PU.1-/- fetal liver at e14.5 lacked common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs) but retained megakaryocyteerythroid progenitors (MEPs). Consistent with the loss of HSC activity, a 10-fold reduction in erythroid progenitors (mature erythroid burst-forming units [BFUEs]) was observed between e14.5 and e16.5. These data suggest that PU.1 plays an important role in the maintenance or expansion of HSC number in murine fetal liver. (Blood. 2004;104:3894-3900)
- Published
- 2004
22. Pax5 determines B- versus T-cell fate and does not block early myeloid-lineage development
- Author
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Claudiu V. Cotta, Christopher A. Klug, Zheng Zhang, and Hyung-Gyoon Kim
- Subjects
Myeloid ,T cell ,Cellular differentiation ,T-Lymphocytes ,Immunology ,Biology ,Biochemistry ,Mice ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Animals ,Cell Lineage ,Myeloid Cells ,Lymphopoiesis ,B-Lymphocytes ,Multipotent Stem Cells ,PAX5 Transcription Factor ,Cell Biology ,Hematology ,Hematopoietic Stem Cells ,Cell biology ,DNA-Binding Proteins ,Killer Cells, Natural ,Mice, Inbred C57BL ,Haematopoiesis ,medicine.anatomical_structure ,Leukopoiesis ,Bone marrow ,Myelopoiesis ,Stem cell ,Transcription Factors - Abstract
Progenitor B cells deficient in Pax5 are developmentally multipotent, suggesting that Pax5 is necessary to maintain commitment to the B-cell lineage. Commitment may be mediated, in part, by Pax5 repression of myeloid-specific genes. To determine whether Pax5 expression in multipotential cells is sufficient to restrict development to the B-cell lineage in vivo, we enforced expression of Pax5 in hematopoietic stem cells using a retroviral vector. Peripheral blood analysis of all animals reconstituted with Pax5-expressing cells indicated that more than 90% of Pax5-expressing cells were B220+ mature B cells that were not malignant. Further analysis showed that Pax5 completely blocked T-lineage development in the thymus but did not inhibit myelopoiesis or natural killer (NK) cell development in bone marrow. These results implicate Pax5 as a critical regulator of B- versus T-cell developmental fate and suggest that Pax5 may promote commitment to the B-cell lineage by mechanisms that are independent of myeloid gene repression.
- Published
- 2003
23. Prognostic Significance of Histone (H4) Acetylation In Newly Diagnosed Acute Myeloid Leukemia (AML) Patients with Intermediate Risk Cytogenetics
- Author
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Anjali S. Advani, Yogen Saunthararajah, Mazyar Shadman, Mikkael A. Sekeres, Eric D. Hsi, Ronald Sobecks, Matt Kalaycio, Edward A. Copelan, Sarah Gibson, Meagan Effinger, and Claudiu V. Cotta
- Subjects
Oncology ,education.field_of_study ,medicine.medical_specialty ,Immunology ,Population ,Myeloid leukemia ,Induction chemotherapy ,Cancer ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,Histone H4 ,Leukemia ,medicine.anatomical_structure ,Internal medicine ,medicine ,Cytarabine ,Bone marrow ,education ,medicine.drug - Abstract
Abstract 2736 Background: Epigenetic instability and aberrant repression of tumor suppressor genes are fundamental aspects of acute myeloid leukemia (AML) biology. Current prognostic assays for AML focus on the genetic aspects of disease biology, for example, chromosome abnormalities and recurrent mutations. We hypothesized that a simple assay for an epigenetic abnormality can address the epigenetic domain of AML, with implications for prognostication and for treatment selection with chromatin relaxing drugs. We focused on patients with intermediate risk cytogenetics (CG) and evaluated the association between histone (H4) acetylation and complete remission (CR), relapse-free survival (RFS), and overall survival (OS) in newly diagnosed AML patients with intermediate risk CG. Methods: We assessed histone H4 acetylation status in bone marrow biopsies from newly diagnosed AML patients with intermediate risk CG treated at our institution between the years 2003–2005. CG risk group was ascribed per Cancer and Leukemia Group B criteria. Association with CR, RFS and OS was assessed using logistic regression and Cox proportional hazard regression models. Variables used in the multivariate models included: age, WBC at diagnosis, gender, and history of antecedent hematologic disorder (AHD). B5-fixed bone marrow core biopsies were reviewed for areas with the highest blast concentration. Immunohistochemistry was performed for acetyl-H4 (1:200 dilution; polyclonal; Upstate Biotech, Lake Placid, NY) using automated stainers and heat-induced epitope retrieval. In each case, five hundred blasts were counted and only strong nuclear staining was classified as positive. Based on the distribution of cell counts, cases were classified as strongly positive if nuclear staining occurred in > 80% of the blasts. Results: Forty-two patients had intermediate risk CG and received cytarabine-based induction chemotherapy. The median age was 56.5 years (range 17–79) and median WBC count at diagnosis was 10.9 × 109/L (range 0.8– 227.9). Twenty two percent of patients had an AHD. Thirty three patients (78%) had normal cytogenetics. Chromosomal abnormalities +8,+21, and 11q23 abnormalities were present in 3 (7.1%), 1 (2.3%) and 4 (9.4%) patients, respectively. FLT3 status was available on only 9 patients; with 7 patients having no FLT3 mutations. Twelve patients (28.5%) received an allogeneic bone marrow transplant in first remission. The median follow-up time was 22.4 months (range 0.6–65.3). Thirty-four patients (81%) achieved CR. Using the 80% cut-off, 15 patients (35.7%) were positive for histone H4 acetylation. Histone (H4) acetylation was not associated with achievement of CR (OR=3.0, 95% CI 0.3–25.3, p=0.3). However, on multivariate analysis, a significant association was found between histone acetylation and risk of relapse (HR 0.34, 95% CI 0.11–0.99, p=0.05) and overall survival (HR=0.34, 95% CI 0.15–0.80, p=0.01). Inclusion of allogeneic transplant in the multivariate models did not change these estimates. Conclusion: Histone H4 acetylation is associated with improved RFS and OS in newly diagnosed AML patients with intermediate risk CG. These results will need to be validated in a larger population of uniformly treated patients. However, histone H4 acetylation has the potential as a simple assay to assess for the contribution of abnormal epigenetics to AML biology, with prognostic and potentially therapeutic implications, given the increasing role of epigenetically targeted therapy in myeloid malignancy management. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2010
24. Bortezomib for ITP: First Report of Successful Treatment of Refractory ITP In a Patient with Otherwise Asymptomatic Monoclonal Gammopathy
- Author
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Janice Reed, Claudiu V. Cotta, Robert M. Dean, Aleksandr Lazaryan, Keith R. McCrae, Frederic J. Reu, and Alan E. Lichtin
- Subjects
medicine.diagnostic_test ,business.industry ,Bortezomib ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Thalidomide ,Bone marrow examination ,medicine.anatomical_structure ,immune system diseases ,hemic and lymphatic diseases ,Medicine ,Rituximab ,Bone marrow ,business ,Dexamethasone ,Monoclonal gammopathy of undetermined significance ,medicine.drug ,Lenalidomide - Abstract
Abstract 4667 Current concepts of the pathophysiology of primary immune thrombocytopenia (ITP) reflect a complex interplay between antiplatelet antibodies, cytotoxic T-lymphocytes (CTL), T regulatory cells, and impaired bone marrow megakaryopoiesis. The mechanisms of ITP in the presence of monoclonal gammopathy of unknown significance (MGUS), a form of secondary ITP, are less well understood, yet treatment has been essentially the same as for primary ITP. Inhibition of antiplatelet CTL responses through apoptosis induction in clonal antiplatelet-antibody producing plasma cells and proteasome inhibition in CTLs may be achieved with bortezomib. However, bortezomib may cause transient isolated thrombocytopenia via presumed inhibition of marrow thrombopoiesis or enhanced platelet clearance peripherally. We used bortezomib in a 55 year-old female with IgG lambda monoclonal gammopathy and ITP refractory to previous treatment with corticosteroids, intravenous immunoglobulin, splenectomy, danazole, and rituximab, none of which induced a durable increase in her platelet counts to hemostatic concentrations. She suffered from repeated episodes of prolonged epistaxis, and when the platelet count fell below 10K/mm3, she experienced a life-threatening gastrointestinal hemorrhage. Otherwise, she had no anemia, her creatinine and calcium remained normal throughout, and skeletal surveys showed no evidence for myeloma. Repeated bone marrow examinations, reviewed at our institution, demonstrated lambda monotypic plasma cells always below 10%, and a normal female karyotype on metaphase cytogenetics. Her thrombocytopenia and bleeding episodes improved transiently on dexamethasone/IMiD combinations (thalidomide followed by lenalidomide), with concurrent reduction in total IgG by almost 50% (M-spike was not measured prior to IMiDs), however she became intolerant to thalidomide due to peripheral neuropathy and experienced diarrhea on lenalidomide. Her platelets decreased and her epistaxis worsened as her m-spike increased on dexamethasone single agent. We thus focused our treatment approach on more robust suppression of the monoclonal protein and initiated a course of weekly bortezomib (1.3 mg/m2), with dexamethasone (20 mg) on the day of and the day after bortezomib. After one month of therapy, the platelet count normalized, and she had no further bleeding episodes. The bortezomib dose was reduced to 1 mg/m2 and dexamethasone reduced to 20 mg weekly after 2 months, with persistently normal platelet counts thereafter. Her ITP resolution on bortezomib was accompanied by a decrease of her serum M-protein from 1.04 to 0.39 g/dL. This case illustrates that bortezomib can be remarkably effective in refractory ITP with concurrent monoclonal gammopathy. Assuming similar pathophysiology, it might also have efficacy in primary refractory ITP. This case also raises the question of whether refractory ITP in the presence of a clonal plasma cell disorder should be considered as a myeloma defining symptom. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2010
25. Strong Histone (H4) Acetylation Is Independently Associated with Better Overall Survival in Newly Diagnosed Acute Myeloid Leukemia (AML)
- Author
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Matt Kalaycio, Ronald Sobecks, Meagan Effinger, Yogen Saunthararajah, Edward A. Copelan, Claudiu V. Cotta, Eric D. Hsi, Mikkael A. Sekeres, Mazyar Shadman, Sarah Gibson, and Anjali S. Advani
- Subjects
Oncology ,medicine.medical_specialty ,Immunology ,Induction chemotherapy ,Myeloid leukemia ,Cancer ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,Histone H4 ,Leukemia ,Internal medicine ,Acute lymphocytic leukemia ,medicine ,Cytarabine ,Histone deacetylase ,medicine.drug - Abstract
Abstract 4681 Background Histone acetylation is a post-translational modification used by proteins to regulate specific chromatin functions. Histone deacetylases (HDACs) play a pivotal role in the pathogenesis of a subset of acute myeloid leukemias (AMLs). HDAC inhibitors are currently being evaluated in clinical trials. We have previously demonstrated an association between increased histone H4 acetylation and increased relapse-free survival (RFS) in patients with newly diagnosed acute lymphocytic leukemia (ALL) (Advani et al., ASH abstract #2798, 2007) and improved overall survival (OS) in ALL patients with first relapse (Advani et al., ASH abstract #1482, 2008). Here, we evaluated the association between histone H4 acetylation with achievement of complete remission (CR) and also with RFS and OS in patients with newly diagnosed AML. Methods In this retrospective cohort study, we assessed H4 acetylation status in bone marrow biopsies of newly diagnosed AML patients at the Cleveland Clinic between the years 2003-2005. Association with CR, RFS and OS was assessed using univariate and multivariate logistic regression and cox-proportional hazard regression models. Variables used in the models included: age and WBC at diagnosis, gender, cytogenetic (CG) risk group, and history of antecedent hematologic disorder (AHD). CG risk group was ascribed per Cancer and Leukemia Group B criteria. B5-fixed bone marrow core biopsies were reviewed for areas of highest blast concentration. Immunohistochemistry was performed for acetyl-H4 (1:200 dilution; polyclonal; Upstate Biotech, Lake Placid, NY) using automated stainers and heat induced epitope retrieval. In each case, five hundred blasts were counted and only strong nuclear staining was classified as positive. Based on the distribution of cell counts, cases were classified as strongly positive if nuclear staining occurred in > 80% of the blasts. Results Eighty-one patients had adequate tissue and clinical data available. We restricted the analysis to sixty patients who received standard induction chemotherapy with cytarabine and an anthracycline. The median age was 58 years (range 20-79) and median WBC was 8.85 × 109/ L (range 0.8-227.9). Seven patients (11.6%) had favorable CG, 41 (68.3%) had intermediate, and 12 (20%) had poor risk CG. Thirty two percent of patients had an AHD. Thirteen patients (21.6%) received an allogeneic bone marrow transplant in first remission. The median follow-up time was 25.5 months (range 2.1-70.6). Forty five patients (75%) achieved CR and the median OS was 12.7 months (range 0.4-70.6). Using the 80% cut-off, 19 patients (31.6%) were positive for H4-acetylation. Histone (H4) acetylation was not associated with achievement of CR (OR=4.1, 95% CI 0.7-24.5, p=0.1) or relapse-free survival (HR 0.62, 95% CI 0.18-2.08, p=0.44). However, in multivariate analysis, histone acetylation was associated with a significantly better OS (HR=0.51, 95% CI 0.29-0.88, p=0.01). Inclusion of allogeneic transplant in the multivariate models did not change these estimates. Conclusion Strongly positive histone (H4) acetylation is associated with better OS in multi-variate analysis. The results mimic our previous findings in ALL patients. Further studies will need to include FLT3 and NPM status in patients with normal cytogenetics in the multi-variate model. These results provide a rationale for AML regimens incorporating HDAC inhibitors, and use of this assay as a potentially relevant biomarker during HDAC inhibitor therapy. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2009
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