KIT is a unique receptor with important functional roles in melanocytes, germ cells, interstitial cells of Cajal, mast cells, and hematopoietic stem cells. Consistent with the importance of KIT in these defined tissues, activating mutations of KIT have been described in germ cell tumors, gastrointestinal stromal tumors (GISTs), sinonasal lymphomas, acute myeloid leukemia (AML), and systemic mastocytosis (SM). A significant proportion of these diseases commonly bear the KIT activation loop mutation KITD816V. Activation loop mutations of KIT have also been observed in core binding factor-acute myeloid leukemia (CBF-AML), leukemias that bear either the t(8;21) or inv(16) cytogenetic abnormality, generating the fusion genes AML1- ETO or CBF?-MYH11, respectively. Studies examining both adult and pediatric AML have indicated that the presence of the KITD816V mutation in CBF-AML carrying t(8;21) worsens the prognosis based on several clinical indices. Although KIT mutations within the juxtamembrane region that are commonly found in GISTs are sensitive to inhibition by the tyrosine kinase inhibitor, imatinib mesylate (Gleevec);KIT mutations within the carboxy-terminal lobe of the tyrosine kinase domain, such as KITD816V, stabilizes the KIT activation loop conformation in its active form, which precludes sufficient imatinib binding for tyrosine kinase inhibition. Therefore, in contrast to successful use of Gleevec to treat GISTs, Gleevec is ineffective for the treatment of the hematologic diseases harboring the KIT activation loop mutants (i.e. KITD816V), including SM and CBF- AML. Importantly, nature of the receptor proximal and/or downstream signals by which activation loop mutations in KIT (KITD816V) induce transformation in primary hematopoietic cells are poorly defined. We have evidence to demonstrate that KITD816V (KITD814V in mice) induced transformation in primary hematopoietic stem and progenitor cells results in constitutive activation of GEF Vav/Rho GTPase Rac pathway and that genetic disruption of hematopoietic specific Vav1 and/or Rac2 in mice abrogates ligand independent growth via KITD814V, leading us to hypothesize that signals involved in KITD814V induced transformation may in part be mediated via the hyperactivation of this pathway. Furthermore, we have evidence demonstrating that mutating the tyrosine residues within the intracellular domain of KITD814V results in complete loss of KITD814V induced ligand independent growth, leading us to hypothesize that the intracellular tyrosines within the juxtamembrane and the kinase insert region of KITD814V are likely to contribute to KITD814V induced transformation. Based on these findings, the central hypothesis of this application is that hyperactivation of the Vav/Rac pathway contributes to the etiology of diseases associated with systemic mastocytosis, AML as well as other diseases involving the KITD814V mutation. Our proposed studies will provide mechanistic insight into the physiologic significance of the Vav/Rac pathway as well as the involvement of the juxtamembrane and the kinase insert sequences in regulating KITD814V induced transformation for which currently no drugs exist.
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.
|Pandey, Ruchi; Kapur, Reuben (2018) Kinase inhibitors in clinical practice: An expanding world. J Allergy Clin Immunol 141:522-524|
|Palam, Lakshmi Reddy; Mali, Raghuveer Singh; Ramdas, Baskar et al. (2018) Loss of epigenetic regulator TET2 and oncogenic KIT regulate myeloid cell transformation via PI3K pathway. JCI Insight 3:|
|Chen, Sisi; Gao, Rui; Kobayashi, Michihiro et al. (2017) Pharmacological inhibition of AKT activity in human CD34+cells enhances their ability to engraft immunodeficient mice. Exp Hematol 45:74-84|
|Pandey, Ruchi; Saxena, Mallika; Kapur, Reuben (2017) Role of SHP2 in hematopoiesis and leukemogenesis. Curr Opin Hematol 24:307-313|
|Ghosh, Joydeep; Kapur, Reuben (2017) Role of mTORC1-S6K1 signaling pathway in regulation of hematopoietic stem cell and acute myeloid leukemia. Exp Hematol 50:13-21|
|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|
|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|
|Kapur, Reuben; Shi, Jianjian; Ghosh, Joydeep et al. (2016) ROCK1 via LIM kinase regulates growth, maturation and actin based functions in mast cells. Oncotarget 7:16936-47|
|Pandey, Ruchi; Kapur, Reuben (2015) Targeting phosphatidylinositol-3-kinase pathway for the treatment of Philadelphia-negative myeloproliferative neoplasms. Mol Cancer 14:118|
|Chatterjee, Anindya; Ghosh, Joydeep; Kapur, Reuben (2015) Mastocytosis: a mutated KIT receptor induced myeloproliferative disorder. Oncotarget 6:18250-64|
Showing the most recent 10 out of 18 publications