Novel Mechanisms of C-Kit Regulation in Mast Cells

Summary

Principal Investigator: Reuben Kapur
Abstract: DESCRIPTION (provided by applicant): Myeloproliferative neoplasms or MPNs are a heterogeneous group of complex hematologic diseases, which share the common characteristic of myeloid cell overproduction. Mastocytosis, especially the systemic form of the disease, also known as systemic mastocytosis (SM) is considered a particularly difficult form of MPN to treat. Activating mutations of KIT are found in over 90% patients with SM, characterized by clonal expansion and accumulation of myelomastocytic progenitors within various tissues leading to organ failure and poor overall survival. With the exception of chronic myelogenous leukemia (CML), there are no effective therapies for MPNs. In the case of CML, targeting the tyrosine kinase BCR-ABL with imatinib (gleevec) or second generation tyrosine kinase (TK) inhibitors such as nilotinib and desatinib appears to be sufficient for treating most patients;however, a significant number of these patients go on to develop drug resistance. In contrast, in other types of MPNs, including SM, targeting the activated version of the receptor tyrosine kinase receptor KIT alone has been ineffective;particularly in patients that harbor the activating mutation of KIT in the catalytic domain, KITD816V, which are completely resistant to imatinib or second generation tyrosine kinase inhibitors. Recent studies in patients with mastocytosis have shown the presence of Tet2 mutations in ~30% patients. In these patients, mutations in Tet2 are associated with higher leukocyte counts, monocyte counts, serum tryptase levels, mast cell burden, splenomegaly and the presence of activating KIT mutation, KITD816V. Thus, Tet2 mutations are frequent in SM;they segregate with KITD816V and significantly influence the phenotype including overall survival and may help explain why anti-KITD816V therapy alone may not be effective for treating these patients. Our long range goal is to elucidate the aberrant signaling mechanism(s) induced by activating KIT mutations and epigenetic regulators such as Tet2 that promote pathologic over production of myeloid/mast cells in SM, with the intent of defining novel therapeutic targets for this disease. The objective of this application is to define the role of Tet2 and activating mutation of KIT and downstream pathways in the initiation and progression of mast cell growth, development and transformation utilizing state of the art mouse genetic models of SM and primary patient samples. Our proposed studies will provide unique insights into the physiologic significance of the in vivo interactions between Tet2 and the oncogenic KIT in regulating normal as well as abnormal myeloid/mast cell biology.
Funding Period: 2004-07-01 - 2017-04-30
more information: NIH RePORT

Top Publications

  1. pmc Genetic and pharmacologic evidence implicating the p85 alpha, but not p85 beta, regulatory subunit of PI3K and Rac2 GTPase in regulating oncogenic KIT-induced transformation in acute myeloid leukemia and systemic mastocytosis
    Veerendra Munugalavadla
    Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Blood 110:1612-20. 2007
  2. ncbi Role of intracellular tyrosines in activating KIT-induced myeloproliferative disease
    P Ma
    Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Leukemia 26:1499-506. 2012
  3. pmc p85β regulatory subunit of class IA PI3 kinase negatively regulates mast cell growth, maturation, and leukemogenesis
    Subha Krishnan
    Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Blood 119:3951-61. 2012
  4. pmc Genetic evidence for critical roles of P38α protein in regulating mast cell differentiation and chemotaxis through distinct mechanisms
    Ping Hu
    Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    J Biol Chem 287:20258-69. 2012
  5. pmc SH2 domain-containing phosphatase 2 is a critical regulator of connective tissue mast cell survival and homeostasis in mice
    Namit Sharma
    Department of Biomedical and Molecular Sciences, Division of Cancer Biology and Genetics, Queen s University, Kingston, Ontario, Canada
    Mol Cell Biol 32:2653-63. 2012
  6. pmc Role of SHP2 phosphatase in KIT-induced transformation: identification of SHP2 as a druggable target in diseases involving oncogenic KIT
    Raghuveer Singh Mali
    Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Blood 120:2669-78. 2012
  7. pmc p38α protein negatively regulates T helper type 2 responses by orchestrating multiple T cell receptor-associated signals
    Ping Hu
    Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    J Biol Chem 287:33215-26. 2012
  8. pmc Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL
    Qiang Wen
    Division of Hematology Oncology, Northwestern University, Chicago, IL 60611, USA
    Cell 150:575-89. 2012
  9. pmc ROCK1 functions as a critical regulator of stress erythropoiesis and survival by regulating p53
    Sasidhar Vemula
    Department of Pediatrics, Herman B Wells Center for Pediatric Research, University School of Medicine, Indianapolis, IN 46202, USA
    Blood 120:2868-78. 2012
  10. pmc The protein tyrosine phosphatase, Shp2, positively contributes to FLT3-ITD-induced hematopoietic progenitor hyperproliferation and malignant disease in vivo
    S C Nabinger
    Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Leukemia 27:398-408. 2013

Research Grants

  1. Novel therapeutic targets for Leukemia in Elderly
    Holly Martin; Fiscal Year: 2013
  2. Experimental Therapeutics of Leukemia
    John C Byrd; Fiscal Year: 2013
  3. MPD RESEARCH CONSORTIUM
    Ronald Hoffman; Fiscal Year: 2013
  4. M D Anderson Cancer Center Prosate SPORE
    Christopher J Logothetis; Fiscal Year: 2013
  5. M. D. Anderson Cancer Center SPORE in Multiple Myeloma
    ROBERT ZYGMUNT ORLOWSKI; Fiscal Year: 2013
  6. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
  7. Bypassing Oncogene Addiction: Mechanisms of off-target resistance in CML
    GABRIEL ANTHONY REYES; Fiscal Year: 2013
  8. Targeted Therapies in Melanoma
    MEENHARD FOLKENS HERLYN; Fiscal Year: 2013
  9. Novel Myeloid Cell Transforming Properties of Interleukin-27 Receptor
    Gary W Reuther; Fiscal Year: 2013
  10. Targeting BCL6 in tyrosine kinase-driven leukemia
    MARKUS MUSCHEN; Fiscal Year: 2013

Detail Information

Publications24

  1. pmc Genetic and pharmacologic evidence implicating the p85 alpha, but not p85 beta, regulatory subunit of PI3K and Rac2 GTPase in regulating oncogenic KIT-induced transformation in acute myeloid leukemia and systemic mastocytosis
    Veerendra Munugalavadla
    Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Blood 110:1612-20. 2007
    ..Taken together, our results identify p85 alpha and Rac2 as potential novel therapeutic targets for the treatment of KITD814V-bearing AML and SM...
  2. ncbi Role of intracellular tyrosines in activating KIT-induced myeloproliferative disease
    P Ma
    Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Leukemia 26:1499-506. 2012
    ..Our results identify critical signaling molecules involved in regulating KITD814V-induced MPD, which might be useful for developing novel therapeutic targets for hematologic malignancies involving this mutation...
  3. pmc p85β regulatory subunit of class IA PI3 kinase negatively regulates mast cell growth, maturation, and leukemogenesis
    Subha Krishnan
    Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Blood 119:3951-61. 2012
    ..Thus, p85α and p85β differentially regulate SCF and oncogenic KIT-induced signals in myeloid lineage-derived mast cells...
  4. pmc Genetic evidence for critical roles of P38α protein in regulating mast cell differentiation and chemotaxis through distinct mechanisms
    Ping Hu
    Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    J Biol Chem 287:20258-69. 2012
    ....
  5. pmc SH2 domain-containing phosphatase 2 is a critical regulator of connective tissue mast cell survival and homeostasis in mice
    Namit Sharma
    Department of Biomedical and Molecular Sciences, Division of Cancer Biology and Genetics, Queen s University, Kingston, Ontario, Canada
    Mol Cell Biol 32:2653-63. 2012
    ..Thus, SHP2 is a key node in a mast cell survival pathway and a new potential therapeutic target in diseases involving mast cells...
  6. pmc Role of SHP2 phosphatase in KIT-induced transformation: identification of SHP2 as a druggable target in diseases involving oncogenic KIT
    Raghuveer Singh Mali
    Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Blood 120:2669-78. 2012
    ..Our results demonstrate that SHP2 phosphatase is a druggable target that cooperates with lipid kinases in inducing MPD...
  7. pmc p38α protein negatively regulates T helper type 2 responses by orchestrating multiple T cell receptor-associated signals
    Ping Hu
    Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    J Biol Chem 287:33215-26. 2012
    ..Taken together, p38α regulates multiple T cell receptor-associated signals and negatively influences Th2 differentiation and allergic inflammation...
  8. pmc Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL
    Qiang Wen
    Division of Hematology Oncology, Northwestern University, Chicago, IL 60611, USA
    Cell 150:575-89. 2012
    ..Our findings provide a rationale to support clinical trials of MLN8237 and other inducers of polyploidization and differentiation in AMKL...
  9. pmc ROCK1 functions as a critical regulator of stress erythropoiesis and survival by regulating p53
    Sasidhar Vemula
    Department of Pediatrics, Herman B Wells Center for Pediatric Research, University School of Medicine, Indianapolis, IN 46202, USA
    Blood 120:2868-78. 2012
    ..These findings are expected to offer new perspectives on stress erythropoiesis and may provide a potential therapeutic target in human disease characterized by anemia...
  10. pmc The protein tyrosine phosphatase, Shp2, positively contributes to FLT3-ITD-induced hematopoietic progenitor hyperproliferation and malignant disease in vivo
    S C Nabinger
    Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Leukemia 27:398-408. 2013
    ..These findings demonstrate that Shp2 positively contributes to FLT3-ITD-induced leukemia and suggest that Shp2 inhibition may provide a novel therapeutic approach to AML...
  11. pmc Class I(A) PI3Kinase regulatory subunit, p85α, mediates mast cell development through regulation of growth and survival related genes
    Subha Krishnan
    Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
    PLoS ONE 7:e28979. 2012
    ..Our results suggest that p85α is involved in mast cell development through regulation of expression of growth, survival and cell cycle related genes...
  12. pmc Rho kinase regulates the survival and transformation of cells bearing oncogenic forms of KIT, FLT3, and BCR-ABL
    Raghuveer Singh Mali
    Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, USA
    Cancer Cell 20:357-69. 2011
    ..In summary we describe a pathway involving PI3K/Rho/ROCK/MLC that may contribute to myeloproliferative disease and/or acute myeloid leukemia in humans...
  13. pmc Src family kinase-mediated negative regulation of hematopoietic stem cell mobilization involves both intrinsic and microenvironmental factors
    Jovencio Borneo
    Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Exp Hematol 35:1026-37. 2007
    ..The intracellular signals that contribute to granulocyte colony-stimulating factor (G-CSF) receptor induced stem cell mobilization are poorly characterized...
  14. ncbi Requirement for p85alpha regulatory subunit of class IA PI3K in myeloproliferative disease driven by an activation loop mutant of KIT
    Veerendra Munugalavadla
    Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Exp Hematol 36:301-8. 2008
    ..Although p85alpha is hyperphosphorylated and constitutively bound to KITD814V in cell-line models; the physiologic significance of this biochemical phenomenon in KITD814V-induced transformation is not known...
  15. pmc The p85alpha subunit of class IA phosphatidylinositol 3-kinase regulates the expression of multiple genes involved in osteoclast maturation and migration
    Veerendra Munugalavadla
    Department of Pediatrics, Herman B Wells Center for Pediatric Research, 2 Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    Mol Cell Biol 28:7182-98. 2008
    ..These results highlight the importance of the full-length version of the p85alpha subunit of class I(A) PI3-K in controlling multiple aspects of osteoclast functions...
  16. pmc Distinct roles of stress-activated protein kinases in Fanconi anemia-type C-deficient hematopoiesis
    M Reza Saadatzadeh
    Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Blood 113:2655-60. 2009
    ..Taken together, these data suggest that p38 MAPK, but not JNK, has a critical role in maintaining the engraftment of Fancc(-/-)-reconstituting cells under conditions of stress...
  17. pmc ROCK1 functions as a suppressor of inflammatory cell migration by regulating PTEN phosphorylation and stability
    Sasidhar Vemula
    Department of Pediatrics, Indiana University School of Medicine, Herman B Wells Center for Pediatric Research, Indianapolis, USA
    Blood 115:1785-96. 2010
    ..Our results reveal ROCK1 as a physiologic regulator of PTEN whose function is to repress excessive recruitment of macrophages and neutrophils during acute inflammation...
  18. pmc Essential role for focal adhesion kinase in regulating stress hematopoiesis
    Sasidhar Vemula
    Department of Pediatrics, Indiana University School of Medicine, Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA
    Blood 116:4103-15. 2010
    ..Our studies reveal an essential role for FAK in integrating growth/survival and adhesion based functions in myeloid and erythroid cells predominantly under conditions of stress...
  19. pmc KIT signaling regulates MITF expression through miRNAs in normal and malignant mast cell proliferation
    Youl Nam Lee
    Pediatric Hematology, Johns Hopkins University, 720 Rutland Avenue, Baltimore, MD 21205, USA
    Blood 117:3629-40. 2011
    ..This work demonstrates a novel regulatory pathway between 2 critical mast cell factors, KIT and MITF, mediated by miRNAs; dysregulation of this pathway may contribute to abnormal mast cell proliferation and malignant mast cell diseases...
  20. pmc p85alpha regulates osteoblast differentiation by cross-talking with the MAPK pathway
    Xiaohua Wu
    Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    J Biol Chem 286:13512-21. 2011
    ..These results suggest that p85α plays an essential role in osteoblast differentiation from MSCs by repressing the activation of MAPK pathway...
  21. pmc The PI3K pathway drives the maturation of mast cells via microphthalmia transcription factor
    Peilin Ma
    Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA
    Blood 118:3459-69. 2011
    ..Thus, p85α-induced maturation, and growth and survival signals, in mast cells can be uncoupled...
  22. pmc Balanced interactions between Lyn, the p85alpha regulatory subunit of class I(A) phosphatidylinositol-3-kinase, and SHIP are essential for mast cell growth and maturation
    Peilin Ma
    Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, 1044 W Walnut Street, Indianapolis, IN 46202, USA
    Mol Cell Biol 31:4052-62. 2011
    ..Our results demonstrate a crucial interplay of Lyn, SHIP, and p85α in regulating the normal growth and maturation of BMMCs, in part by regulating the activation of AKT and the expression of Mitf...
  23. pmc PI3K p110δ uniquely promotes gain-of-function Shp2-induced GM-CSF hypersensitivity in a model of JMML
    CHARLES B GOODWIN
    Herman B Wells Center for Pediatric Research
    Blood 123:2838-42. 2014
    ....

Research Grants31

  1. Novel therapeutic targets for Leukemia in Elderly
    Holly Martin; Fiscal Year: 2013
    ..I expect the results of these studies to enhance our understanding of the mechanism of KITD816V-induced transformation, and potentially provide novel therapeutic targets for oncogenic KIT bearing neoplasms. ..
  2. Experimental Therapeutics of Leukemia
    John C Byrd; Fiscal Year: 2013
    ..We believe that this SPORE group, as a multidisciplinary, highly interactive and accomplished team, will have a substantial impact on improving the clinical outcome of leukemia patients. ..
  3. MPD RESEARCH CONSORTIUM
    Ronald Hoffman; Fiscal Year: 2013
    ..abstract_text> ..
  4. M D Anderson Cancer Center Prosate SPORE
    Christopher J Logothetis; Fiscal Year: 2013
    ..We are optimistic that our research efforts will contribute to reductions in the incidence of, and morbidity and mortality from, this devastating disease by translating basic research into clinical practice. ..
  5. M. D. Anderson Cancer Center SPORE in Multiple Myeloma
    ROBERT ZYGMUNT ORLOWSKI; Fiscal Year: 2013
    ..abstract_text> ..
  6. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
    ..Reflecting our remarkable and continued growth, UMGCC seeks to renew its CCSG to enhance and expand its efforts in high-quality and clinically relevant cancer research. ..
  7. Bypassing Oncogene Addiction: Mechanisms of off-target resistance in CML
    GABRIEL ANTHONY REYES; Fiscal Year: 2013
    ..Additionally, it is hoped that adjunctive therapeutic targets will be identified that may improve treatment outcomes for patients with CML and other malignancies associated with pathologic activation of tyrosine kinases. ..
  8. Targeted Therapies in Melanoma
    MEENHARD FOLKENS HERLYN; Fiscal Year: 2013
    ..To account for the increased needs for compound synthesis and modification, we have added a Medicinal Chemistry Core (D) in this renewal application. ..
  9. Novel Myeloid Cell Transforming Properties of Interleukin-27 Receptor
    Gary W Reuther; Fiscal Year: 2013
    ..The proposed studies are the first to investigate the novel transforming properties of IL27R, which we recently discovered, and will investigate potential novel therapeutic targets for AML. ..
  10. Targeting BCL6 in tyrosine kinase-driven leukemia
    MARKUS MUSCHEN; Fiscal Year: 2013
    ....
  11. Elucidating the roles of ETV1 in the pathogenesis of GIST
    Ping Chi; Fiscal Year: 2013
    ..At the end of the period, my goal is become an independent physician-scientist combining bench based research and clinical care of sarcoma patients. ..
  12. Role of Vav and Rac in KIT oncogenesis
    Reuben Kapur; Fiscal Year: 2013
    ..abstract_text> ..
  13. Immature myeloid cells as targets for therapeutics to bacterial infection
    ADRIANUS WILHELMUS MARIA VAN DER VELDEN; Fiscal Year: 2013
    ..Typhimurium. In Specific Aim 3, we will specifically target MDSC expansion, activation and suppressive activity at the transition from innate to adaptive immune response as a novel therapeutic approach to infection. ..
  14. Role of NF-kB in hematopoietic stem cells and leukemia-initiating cell formation
    Christopher A Klug; Fiscal Year: 2013
    ..This proposal will examine the role of NF-?B in normal hematopoietic stem/progenitor cell function and test whether activation of NF-?B is sufficient to initiate and/or maintain LIC activity in AML. ..
  15. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  16. A Mouse Model for Human Gastrointestinal Stromal Tumor
    Peter Besmer; Fiscal Year: 2013
    ..abstract_text> ..
  17. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  18. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  19. 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. ..
  20. THE FUNCTION AND REGULATION OF HISTIDINE DECARBOXYLASE IN GUT INFLAMMATION
    TIMOTHY CRAGIN WANG; Fiscal Year: 2013
    ..abstract_text> ..
  21. 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. ..
  22. HSC Diversity: Regulation by Clonal Selection vs Epigenetic Induction
    Irving L Weissman; Fiscal Year: 2013
    ....
  23. INTEGRATIVE PATHOPHYSIOLOGY OF SOLID TUMORS
    Rakesh K Jain; Fiscal Year: 2013
    ..abstract_text> ..