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.

Public Health Relevance

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)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-VH-D (02))
Program Officer
Di Fronzo, Nancy L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
Zip Code
Bessler, Waylan K; Kim, Grace; Hudson, Farlyn Z et al. (2016) Nf1+/- monocytes/macrophages induce neointima formation via CCR2 activation. Hum Mol Genet 25:1129-39
Ghosh, Joydeep; Kobayashi, Michihiro; Ramdas, Baskar et al. (2016) S6K1 regulates hematopoietic stem cell self-renewal and leukemia maintenance. J Clin Invest 126:2621-5
Richine, B M; Virts, E L; Bowling, J D et al. (2016) Syk kinase and Shp2 phosphatase inhibition cooperate to reduce FLT3-ITD-induced STAT5 activation and proliferation of acute myeloid leukemia. Leukemia 30:2094-2097
Gao, Rui; Chen, Sisi; Kobayashi, Michihiro et al. (2015) Bmi1 promotes erythroid development through regulating ribosome biogenesis. Stem Cells 33:925-38
Pandey, Ruchi; Kapur, Reuben (2015) Targeting phosphatidylinositol-3-kinase pathway for the treatment of Philadelphia-negative myeloproliferative neoplasms. Mol Cancer 14:118
Zhang, Jilu; Ramadan, Abdulraouf M; Griesenauer, Brad et al. (2015) ST2 blockade reduces sST2-producing T cells while maintaining protective mST2-expressing T cells during graft-versus-host disease. Sci Transl Med 7:308ra160
Mantel, Charlie R; O'Leary, Heather A; Chitteti, Brahmananda R et al. (2015) Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock. Cell 161:1553-65
Chatterjee, Anindya; Ghosh, Joydeep; Kapur, Reuben (2015) Mastocytosis: a mutated KIT receptor induced myeloproliferative disorder. Oncotarget 6:18250-64
Onishi, Chie; Mori-Kimachi, Satomi; Hirade, Tomohiro et al. (2015) Internal tandem duplication mutations in FLT3 gene augment chemotaxis to Cxcl12 protein by blocking the down-regulation of Rho-associated kinase via the Cxcl12/Cxcr4 signaling axis. J Biol Chem 290:28356
Sharma, Namit; Everingham, Stephanie; Ramdas, Baskar et al. (2014) SHP2 phosphatase promotes mast cell chemotaxis toward stem cell factor via enhancing activation of the Lyn/Vav/Rac signaling axis. J Immunol 192:4859-66

Showing the most recent 10 out of 51 publications