Training/Research Center-Bone Marrow Failure Syndromes

Summary

Principal Investigator: Jaroslaw P Maciejewski
Abstract: DESCRIPTION (provided by applicant): Bone marrow failure (BMF) syndromes, including aplastic anemia (AA) and myelodysplasia (MDS) are disorders characterized by hematopoietic progenitor or stem cell failure resulting in deficient production of one or all blood cell lineages. Immune pathophysiology and propensity for clonal evolution are the unifying factors in these diseases that can be otherwise very heterogenous. Laboratory and clinical studies are needed to better understand the pathophysiology and etiology of MDS and AA with the goal of development of improved diagnostic tools and treatment approaches. In particular our research training program focuses on application of novel molecular technologies to elucidate molecular and immune pathogenesis of bone marrow failure. Research projects which form solid research and clinical foundation of this proposal target diverse topics and include several RO1s. For example, we will investigate chromosomal lesions in bone marrow failure using single nucleotide polymorphism arrays (SNP-A) which as a high resolution karyotyping method allows for the detection of unbalanced DNA defects, including somatic uniparental disomy (UPD) and thereby reveal previously cryptic defects. Detection of such lesions could facilitate identification of novel therapeutic targets, aid diagnosis and improve current prognostic schemes by explaining the phenotypic heterogeneity of MDS. We have demonstrated that somatic UPD is very frequent in MDS and hypothesized that shared regions of UPD may point towards mutations of genes involved in the development of MDS. We mapped invariant UPD and deletions in a large group of patients with MDS and found that UPD11q was particularly frequent in patients with MDS and CMML. Sequencing of this region demonstrated mutations in c-Cbl, an E3 ubiquitin ligase. These research and other related research activities will serve as a basis for continuation of our K24 (BMF) training program which integrates young physician scientists into the clinical and translational research teams and stimulate interest in an academic career path as clinical investigators. Our proposal encompasses a multitargeted approach involving: 1) Systematic evaluation of novel laboratory assays that may improve diagnostic accuracy or understanding of pathophysiologic mechanisms in bone marrow failure;2) Development of experimental treatment protocols for disease subsets without good treatment options or without a standard treatment approach, 3) Training of post-doctoral fellows to develop clinical trials and translational research projects within the bone marrow failure center, 4) Integration of basic scientists into clinical research and physicians from related disciplines to form productive research teams in the field of bone marrow failure syndromes. The expertise of the principal investigator, together with the experience, size and facilities at CC uniquely fits with the spirit of the K24 award program and would allow Dr. Jaroslaw Maciejewski to commit more time and effort to clinical research and training while continuing creation of a strong research program. NARRATIVE: Myelodysplastic syndromes (MDS) is a heterogeneous group of bone marrow failure states characterized by dysplastic hematopoiesis, deficient blood cell production and a propensity to progression to acute myelogenous leukemia (AML);this heterogeneity has greatly impeded investigations into the molecular pathogenesis and potential therapies for these diseases. We propose that single nucleotide polymorphisms arrays (SNP-A) can be applied, complementary to metaphase cytogenetics for the identification of chromosomal abnormalities, including a newly recognized class of lesion, somatic uniparental disomy. We will precisely map these lesions, identifying genes that may play a role in the disease and potentially act as targets of therapy;these studies will form the basis for the training program proposed.
Funding Period: 2004-07-01 - 2015-04-30
more information: NIH RePORT

Top Publications

  1. pmc Emerging roles of the spliceosomal machinery in myelodysplastic syndromes and other hematological disorders
    V Visconte
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
    Leukemia 26:2447-54. 2012
  2. pmc Casitas B-cell lymphoma mutation in childhood T-cell acute lymphoblastic leukemia
    Yuka Saito
    Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan
    Leuk Res 36:1009-15. 2012
  3. pmc Somatic STAT3 mutations in large granular lymphocytic leukemia
    Hanna L M Koskela
    Hematology Research Unit Helsinki, Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
    N Engl J Med 366:1905-13. 2012
  4. pmc Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis
    Andres Jerez
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
    Blood 119:6109-17. 2012
  5. pmc Cytogenetic and molecular predictors of response in patients with myeloid malignancies without del[5q] treated with lenalidomide
    Yuka Sugimoto
    Department of Translational Hematology and Oncology Research, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA
    J Hematol Oncol 5:4. 2012
  6. pmc Topography, clinical, and genomic correlates of 5q myeloid malignancies revisited
    Andres Jerez
    Cleveland Clinic, Cleveland, OH, USA
    J Clin Oncol 30:1343-9. 2012
  7. pmc Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis
    Hideki Makishima
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
    Blood 119:3203-10. 2012
  8. ncbi CBL mutation-related patterns of phosphorylation and sensitivity to tyrosine kinase inhibitors
    H Makishima
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Leukemia 26:1547-54. 2012
  9. ncbi Molecular lesions in childhood and adult acute megakaryoblastic leukaemia
    Asahito Hama
    Department of Paediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
    Br J Haematol 156:316-25. 2012
  10. pmc Spliceosomal gene mutations are frequent events in the diverse mutational spectrum of chronic myelomonocytic leukemia but largely absent in juvenile myelomonocytic leukemia
    Sarah Abu Kar
    Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, Ohio, USA
    Haematologica 98:107-13. 2013

Research Grants

  1. Molecular Pathogenesis of MDS and CMML
    Jaroslaw P Maciejewski; Fiscal Year: 2013
  2. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
  3. PAPOVA VIRUS TRANSFORMING MECHANISMS
    DAVID MORSE LIVINGSTON; Fiscal Year: 2013
  4. Characterization of Genetic Abnormalities in MDS and Their Clinical Impact
    Rafael Bejar; Fiscal Year: 2013
  5. Molecular Pathways to Thynmic Lymphoma and Leukemia
    A Thomas Look; Fiscal Year: 2013

Detail Information

Publications55

  1. pmc Emerging roles of the spliceosomal machinery in myelodysplastic syndromes and other hematological disorders
    V Visconte
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
    Leukemia 26:2447-54. 2012
    ....
  2. pmc Casitas B-cell lymphoma mutation in childhood T-cell acute lymphoblastic leukemia
    Yuka Saito
    Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan
    Leuk Res 36:1009-15. 2012
    ..The activation of the RAS pathway was enhanced, and activation of the NOTCH1 pathway was inhibited in NIH 3T3 cells that expressed p.C381R. This study appears to be the first to identify a CBL mutation in T-ALL...
  3. pmc Somatic STAT3 mutations in large granular lymphocytic leukemia
    Hanna L M Koskela
    Hematology Research Unit Helsinki, Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
    N Engl J Med 366:1905-13. 2012
    ....
  4. pmc Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis
    Andres Jerez
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
    Blood 119:6109-17. 2012
    ....
  5. pmc Cytogenetic and molecular predictors of response in patients with myeloid malignancies without del[5q] treated with lenalidomide
    Yuka Sugimoto
    Department of Translational Hematology and Oncology Research, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA
    J Hematol Oncol 5:4. 2012
    ..We hypothesized that improved detection of chromosomal abnormalities with new karyotyping tools may better predict response to LEN...
  6. pmc Topography, clinical, and genomic correlates of 5q myeloid malignancies revisited
    Andres Jerez
    Cleveland Clinic, Cleveland, OH, USA
    J Clin Oncol 30:1343-9. 2012
    ....
  7. pmc Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis
    Hideki Makishima
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
    Blood 119:3203-10. 2012
    ..Spliceosomal genes are probably tumor suppressors, and their mutations may constitute diagnostic biomarkers that could potentially serve as therapeutic targets...
  8. ncbi CBL mutation-related patterns of phosphorylation and sensitivity to tyrosine kinase inhibitors
    H Makishima
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Leukemia 26:1547-54. 2012
    ..In conclusion, the promiscuous effects of CBL loss on SFK and RTK signaling appear to be best targeted by dual SFK and RTK inhibition...
  9. ncbi Molecular lesions in childhood and adult acute megakaryoblastic leukaemia
    Asahito Hama
    Department of Paediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
    Br J Haematol 156:316-25. 2012
    ..ASXL1, IDH1/2, DNMT3A, RUNX1 and CBL mutations were not found in any of the patient group studied, while NRAS mutation was identified in two patients with paediatric non-DS-AMKL...
  10. pmc Spliceosomal gene mutations are frequent events in the diverse mutational spectrum of chronic myelomonocytic leukemia but largely absent in juvenile myelomonocytic leukemia
    Sarah Abu Kar
    Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, Ohio, USA
    Haematologica 98:107-13. 2013
    ..Our data also suggest that spliceosomal mutations are of ancestral origin...
  11. pmc SF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes
    Valeria Visconte
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, OH, USA
    Blood 120:3173-86. 2012
    ..In conclusion, we report the first experimental evidence of the association between SF3B1 and RS phenotype. Our data suggest that SF3B1 haploinsufficiency leads to RS formation...
  12. pmc STAT3 mutations indicate the presence of subclinical T-cell clones in a subset of aplastic anemia and myelodysplastic syndrome patients
    Andres Jerez
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
    Blood 122:2453-9. 2013
    ..STAT3-mutant LGL clones may facilitate a persistently dysregulated autoimmune activation, responsible for the primary induction of bone marrow failure in a subset of AA and MDS patients. ..
  13. pmc Somatic SETBP1 mutations in myeloid malignancies
    Hideki Makishima
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA
    Nat Genet 45:942-6. 2013
    ..Somatic mutations of SETBP1 seem to cause gain of function, are associated with myeloid leukemic transformation and convey poor prognosis in myelodysplastic syndromes (MDS) and CMML. ..
  14. pmc Patterns of missplicing due to somatic U2AF1 mutations in myeloid neoplasms
    Bartlomiej Przychodzen
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Blood 122:999-1006. 2013
    ..These novel observations support the hypothesis that U2AF1 mutations play a significant role in myeloid leukemogenesis due to selective missplicing of tumor-associated genes. ..
  15. ncbi A mechanistic overview of TET-mediated 5-methylcytosine oxidation
    V K Chaithanya Ponnaluri
    Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri Kansas City, 64108 MO, United States
    Biochem Biophys Res Commun 436:115-20. 2013
    ..Here, we review the TET-mediated 5mC oxidation in light of the putative reaction mechanism of Fe(II), 2-oxoglutarate-dependent oxygenases. ..
  16. pmc Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia
    Hanna L M Rajala
    Hematology Research Unit Helsinki, Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
    Blood 121:4541-50. 2013
    ..This is the first time somatic STAT5 mutations are discovered in human cancer and further emphasizes the role of STAT family genes in the pathogenesis of LGL leukemia...
  17. ncbi Multiple mechanisms deregulate EZH2 and histone H3 lysine 27 epigenetic changes in myeloid malignancies
    S N Khan
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Leukemia 27:1301-9. 2013
    ..In summary, our results suggest that loss of gene repression through a variety of mutations resulting in reduced H3K27 trimethylation may contribute to leukemogenesis...
  18. ncbi The need for additional genetic markers for myelodysplastic syndrome stratification: what does the future hold for prognostication?
    Zaher K Otrock
    Leukemia Program, Cleveland Clinic Taussig Cancer Institute, OH 44195, USA
    Expert Rev Hematol 6:59-68. 2013
    ..The authors also discuss the recently investigated genetic mutations in MDS and revisit the MDS classification and prognostic scoring systems...
  19. pmc Phase 2 study of the lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic syndromes
    Mikkael A Sekeres
    Leukemia Program, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Ave, Cleveland, OH 44195, USA
    Blood 120:4945-51. 2012
    ..TET2/DNMT3A/IDH1/2 mutational status was associated with response in a limited number of patients. The lenalidomide/azacitidine combination is well-tolerated and highly active in treating greater-risk MDS...
  20. pmc Single nucleotide polymorphism array lesions, TET2, DNMT3A, ASXL1 and CBL mutations are present in systemic mastocytosis
    Fabiola Traina
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
    PLoS ONE 7:e43090. 2012
    ..04) and sole TET2 mutations (P<0.001). In conclusion, TET2, DNMT3A and ASXL1 mutations are also present in mastocytosis and these mutations may affect prognosis, as demonstrated by worse OS in mutated patients...
  21. pmc STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia
    Andres Jerez
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Blood 120:3048-57. 2012
    ..STAT3 mutations may distinguish truly malignant lymphoproliferations involving T and NK cells from reactive expansions...
  22. pmc Clonal drift demonstrates unexpected dynamics of the T-cell repertoire in T-large granular lymphocyte leukemia
    Michael J Clemente
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
    Blood 118:4384-93. 2011
    ..Our results demonstrate that the T-cell repertoire is more dynamic in T-LGLL than recognized previously, illustrating the heterogeneity of disorders under this categorization...
  23. pmc Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A
    Anna M Jankowska
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
    Blood 118:3932-41. 2011
    ..Various mutant genotype combinations were observed, indicating molecular heterogeneity in CMML. Our results suggest that molecular defects affecting distinct pathways can lead to similar clinical phenotypes...
  24. pmc Efficacy of rabbit anti-thymocyte globulin in severe aplastic anemia
    Manuel G Afable
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
    Haematologica 96:1269-75. 2011
    ..We performed a phase II study of rabbit anti-thymocyte globulin and cyclosporine as first-line therapy for severe aplastic anemia...
  25. pmc Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms
    Anna M Jankowska
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, OH 44195, USA
    Blood 113:6403-10. 2009
    ..The frequency of mutations in this candidate myeloid regulatory gene suggests an important role in the pathogenesis of poor prognosis MDS/MPN and sAML and may act as a disease gene marker for these often cytogenetically normal disorders...
  26. pmc 250K single nucleotide polymorphism array karyotyping identifies acquired uniparental disomy and homozygous mutations, including novel missense substitutions of c-Cbl, in myeloid malignancies
    Andrew J Dunbar
    Department of Hematologic Oncology and Blood Disorders, Experimental Hematology and Hematopoiesis Section, Taussig Cancer Center, Cleveland Clinic, Cleveland, Ohio 44195, USA
    Cancer Res 68:10349-57. 2008
    ..Acquired mutations of c-Cbl E3 ubiquitin ligase may explain the pathogenesis of a clonal process in a subset of MDS/MPD, including CMML...
  27. pmc Aberrant DNA methylation is a dominant mechanism in MDS progression to AML
    Ying Jiang
    Experimental Hematology and Hematopoiesis Section, Taussig Cancer Center, Cleveland Clinic, OH 44195, USA
    Blood 113:1315-25. 2009
    ..However, the ubiquity, extent, and correlation with disease progression suggest that aberrant DNA methylation is the dominant mechanism for TSG silencing and clonal variation in MDS evolution to AML...
  28. pmc Clonotype analysis of cytomegalovirus-specific cytotoxic T lymphocytes
    Nina Babel
    Experimental Haematology and Hematopoiesis Section, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio, USA
    J Am Soc Nephrol 20:344-52. 2009
    ..These results provide new insights into the regulation of CMV clonal dominance and may contribute to the design and monitoring of adoptive immunotherapy...
  29. pmc Whole genome scanning as a cytogenetic tool in hematologic malignancies
    Jaroslaw P Maciejewski
    Experimental Hematology and Hematopoiesis Section, Taussig Cancer Center, Cleveland Clinic, OH, USA
    Blood 112:965-74. 2008
    ..Newly detected chromosomal aberrations, including somatic uniparental disomy, may lead to more precise prognostic schemes in many diseases...
  30. ncbi Double-negative regulatory T cells induce allotolerance when expanded after allogeneic haematopoietic stem cell transplantation
    Z McIver
    Experimental Hematology and Hematopoiesis Section, Cleveland, OH 44195, USA
    Br J Haematol 141:170-8. 2008
    ..All individuals who demonstrated more than 1% DN Tregs did not develop GvHD, providing evidence that DN Tregs participate in peripheral tolerance to prevent GvHD when expanded after allogeneic HSCT...
  31. ncbi Base excision repair dysfunction in a subgroup of patients with myelodysplastic syndrome
    A M Jankowska
    Experimental Hematology and Hematopoiesis Section, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH 44195, USA
    Leukemia 22:551-8. 2008
    ....
  32. pmc SNP array karyotyping allows for the detection of uniparental disomy and cryptic chromosomal abnormalities in MDS/MPD-U and MPD
    Lukasz P Gondek
    Experimental Hematology and Hematopoiesis Section, Taussig Cancer Center, Cleveland Clinic, Cleveland, Ohio, United States of America
    PLoS ONE 2:e1225. 2007
    ..SNP-A-based detection of cryptic lesions in MDS/MPD-U may help explain the clinical heterogeneity of this disorder...
  33. pmc Chromosomal lesions and uniparental disomy detected by SNP arrays in MDS, MDS/MPD, and MDS-derived AML
    Lukasz P Gondek
    Experimental Hematology and Hematopoiesis Section, Taussig Cancer Center, Cleveland Clinic, OH, USA
    Blood 111:1534-42. 2008
    ..SNP-A-based karyotyping shows superior resolution for chromosomal defects, including UPD. This technique further complements MC to improve clinical prognosis and targeted therapies...
  34. ncbi Detection of cryptic chromosomal lesions including acquired segmental uniparental disomy in advanced and low-risk myelodysplastic syndromes
    Lukasz P Gondek
    Experimental Hematology and Hematopoiesis Section, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH 44195, USA
    Exp Hematol 35:1728-38. 2007
    ..We hypothesize that more precise methods of chromosomal analysis will detect new/additional cryptic lesions in a higher proportion of MDS patients...
  35. pmc FISH and SNP-A karyotyping in myelodysplastic syndromes: improving cytogenetic detection of del(5q), monosomy 7, del(7q), trisomy 8 and del(20q)
    Hideki Makishima
    Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, OH, USA
    Leuk Res 34:447-53. 2010
    ....
  36. pmc New lesions detected by single nucleotide polymorphism array-based chromosomal analysis have important clinical impact in acute myeloid leukemia
    Ramon V Tiu
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    J Clin Oncol 27:5219-26. 2009
    ..We hypothesized that SNP-A will improve detection of chromosomal defects in AML and that this would enhance the prognostic value of MC...
  37. pmc SNP array-based karyotyping: differences and similarities between aplastic anemia and hypocellular myelodysplastic syndromes
    Manuel G Afable
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
    Blood 117:6876-84. 2011
    ..In sum, our results indicate that SNP-A identify cryptic clonal genomic aberrations in AA and hMDS leading to improved distinction of these disease entities...
  38. pmc CBL, CBLB, TET2, ASXL1, and IDH1/2 mutations and additional chromosomal aberrations constitute molecular events in chronic myelogenous leukemia
    Hideki Makishima
    Department of Translational Hematology and Oncology Research, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA
    Blood 117:e198-206. 2011
    ..2 and 21q22.12 involved tumor associated genes NF1 and RUNX1, respectively. Our results indicate that CBL family, TET2, ASXL1, and IDH family mutations and additional cryptic karyotypic abnormalities can occur in advanced phase CML...
  39. pmc Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies
    Ramon V Tiu
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute Center, Cleveland, OH, USA
    Blood 117:4552-60. 2011
    ..The significant diagnostic and prognostic contributions of SNP-A-detected defects in MDS and related diseases underscore the utility of SNP-A when combined with MC in hematologic malignancies...
  40. pmc Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2
    Myunggon Ko
    Department of Pathology, Harvard Medical School, Immune Disease Institute and Program in Cellular and Molecular Medicine, Children s Hospital Boston, Boston, Massachusetts 02115, USA
    Nature 468:839-43. 2010
    ..Measurement of 5hmC levels in myeloid malignancies may prove valuable as a diagnostic and prognostic tool, to tailor therapies and assess responses to anticancer drugs...
  41. pmc Decitabine maintains hematopoietic precursor self-renewal by preventing repression of stem cell genes by a differentiation-inducing stimulus
    Zhenbo Hu
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
    Mol Cancer Ther 9:1536-43. 2010
    ..Using decitabine to deplete DNMT1 after this early repression phase does not impair progressive differentiation...
  42. pmc Spectrum of mutations in RARS-T patients includes TET2 and ASXL1 mutations
    Hadrian Szpurka
    Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
    Leuk Res 34:969-73. 2010
    ..JAK2V617F/MPLW515L mutations were absent in TET2/ASXL1 mutants, indicating that similar clinical phenotype can be produced by various MPN-associated mutations and that additional unifying lesions may be present in RARS-T...
  43. pmc Copy neutral loss of heterozygosity: a novel chromosomal lesion in myeloid malignancies
    Christine O'Keefe
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Blood 115:2731-9. 2010
    ....
  44. pmc Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations are pathogenic in juvenile myelomonocytic leukemia
    Hideki Muramatsu
    Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, OH 44195, USA
    Blood 115:1969-75. 2010
    ..Our results indicate that mutations in c-Cbl may represent key molecular lesions in JMML patients without RAS/PTPN11 lesions, suggesting analogous pathogenesis to those observed in chronic myelomonocytic leukemia (CMML) patients...
  45. pmc Mutations of e3 ubiquitin ligase cbl family members constitute a novel common pathogenic lesion in myeloid malignancies
    Hideki Makishima
    Taussig Cancer Institute R40, 9500 Euclid Ave, Cleveland OH 44195, USA
    J Clin Oncol 27:6109-16. 2009
    ..We examined the role and frequency of Cbl gene family mutations in MPN and related conditions...
  46. pmc High-resolution genomic arrays facilitate detection of novel cryptic chromosomal lesions in myelodysplastic syndromes
    Ramon Tiu
    Experimental Hematology and Hematopoiesis Section, Cleveland Clinic, Cleveland, Ohio 44195, USA
    Exp Hematol 35:240-51. 2007
    ..Therefore, it is likely that chromosomal defects in myelodysplastic syndromes may be more frequent than predicted by metaphase cytogenetics and new cryptic lesions may be revealed by precise analysis methods...

Research Grants30

  1. Molecular Pathogenesis of MDS and CMML
    Jaroslaw P Maciejewski; Fiscal Year: 2013
    ..We will precisely map these lesions, identifying genes that may play a role in the disease and potentially act as targets of therapy. ..
  2. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  3. PAPOVA VIRUS TRANSFORMING MECHANISMS
    DAVID MORSE LIVINGSTON; Fiscal Year: 2013
    ..The goal of this Program is to continue to shed new light on cellular transformation events that also underpin human cancer development and generate insights that lead to new cancer therapeutic strategies. ..
  4. Characterization of Genetic Abnormalities in MDS and Their Clinical Impact
    Rafael Bejar; Fiscal Year: 2013
    ..Successful completion the specific aims and career development plan outlined in this proposal will allow the candidate to advance his academic career as an independent investigator in the field of hematology. ..
  5. Molecular Pathways to Thynmic Lymphoma and Leukemia
    A Thomas Look; Fiscal Year: 2013
    ..Such interactions are expected to accelerate the pace at which important discoveries are generated in these projects and in the program as a whole. ..