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.

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It is now unequivocal that activating mutations of KIT contribute to germ cell tumors, gastrointestinal stromal tumors (GISTs), sinonasal lymphomas, acute myeloid leukemia (AML), and systemic mastocytosis (SM). Our proposed studies will provide mechanistic insight into the signaling pathways that regulate transformation via an activating KIT mutation for which currently no drugs exist. Our results are expected to provide new targets for molecular therapies for the treatment of diseases such as AML and SM.

National Institute of Health (NIH)
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Special Emphasis Panel (ZRG1)
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Di Fronzo, Nancy L
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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Goodwin, Charles B; Li, Xing Jun; Mali, Raghuveer S et al. (2014) PI3K p110? uniquely promotes gain-of-function Shp2-induced GM-CSF hypersensitivity in a model of JMML. Blood 123:2838-42
Zeng, Li-Fan; Zhang, Ruo-Yu; Yu, Zhi-Hong et al. (2014) Therapeutic potential of targeting the oncogenic SHP2 phosphatase. J Med Chem 57:6594-609
Kumar, Sachin; Xu, Juying; Kumar, Rupali Sani et al. (2014) The small GTPase Rap1b negatively regulates neutrophil chemotaxis and transcellular diapedesis by inhibiting Akt activation. J Exp Med 211:1741-58
Nabinger, S C; Li, X J; Ramdas, B et al. (2013) The protein tyrosine phosphatase, Shp2, positively contributes to FLT3-ITD-induced hematopoietic progenitor hyperproliferation and malignant disease in vivo. Leukemia 27:398-408
Martin, Holly; Mali, Raghuveer Singh; Ma, Peilin et al. (2013) Pak and Rac GTPases promote oncogenic KIT-induced neoplasms. J Clin Invest 123:4449-63
Krishnan, Subha; Mali, Raghuveer Singh; Koehler, Karl R et al. (2012) Class I(A) PI3Kinase regulatory subunit, p85?, mediates mast cell development through regulation of growth and survival related genes. PLoS One 7:e28979
Krishnan, Subha; Mali, Raghuveer Singh; Ramdas, Baskar et al. (2012) p85? regulatory subunit of class IA PI3 kinase negatively regulates mast cell growth, maturation, and leukemogenesis. Blood 119:3951-61
Hu, Ping; Carlesso, Nadia; Xu, Mingjiang et al. (2012) Genetic evidence for critical roles of P38ýý protein in regulating mast cell differentiation and chemotaxis through distinct mechanisms. J Biol Chem 287:20258-69
Ma, Peilin; Vemula, Sasidhar; Munugalavadla, Veerendra et al. (2011) 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. Mol Cell Biol 31:4052-62
Mali, Raghuveer Singh; Ramdas, Baskar; Ma, Peilin et al. (2011) Rho kinase regulates the survival and transformation of cells bearing oncogenic forms of KIT, FLT3, and BCR-ABL. Cancer Cell 20:357-69

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