In adults, bone marrow (BM) is the major site for the continuous production of mature blood cells. Mature blood cells arise from hematopoieic stem cells (HSCs) within the bone marrow cavity. Although, the regulation of HSCs is an extremely popular area of investigation;how this regulation occurs still remains an enigma. It is thought that part of this process involves self-renewal, differentiation and apoptosis or senescence. Although the precise mechanism(s) by which these fates are determined is still unclear, several molecules have been implicated in these processes, including components of the BM microenvironment. The BM microenvironment consists of extracellular matrix proteins as well as cells such as osteoblasts and stromal cells which contribute to the stem/progenitor cell fate by anchoring these cells in the BM cavity and delivering them adhesive signals as well as signals in the form of soluble ligands, including cytokines and chemokines. These signals induce intracellular activation of both the positive regulators of stem cell growth, self-renewal and differentiation as well as negative signals. Some of these pathways, such as those initiated by stem cell factor (SCF), the ligand for KIT, stromal cell derived factor-1 (SDF-1), and thrombopoietin (TPO), induce the activation of phosphatidylinositol 3'kinase (PI3K) and the formation of phosphatidylinositol 3,4,5-trisphosphate (PIP3). How PIP3 levels are regulated in stem/progenitor cells is poorly understood. This is important, as disregulated PIP3 levels in stem/progenitor cells have been shown to result in myeloproliferative disease (MPD) as well as acute myeloid leukemia (AML). Our long-range goal is to understand the signaling mechanisms that control the growth and survival signals in hematopoietic stem and progenitor cells (SC/Ps), including in myeloid lineage derived macrophages and neutrophils. The objective of this application is to determine how components of class IA PI3Kinase contribute to PIP3 induced SC/P cell growth under steady state as well as under stress induced hematopoiesis. Additional objective are to determine the extent to which PIP3 generated by class IA PI3K in SC/Ps is negatively regulated by phosphatases, and what are some of the signaling mechanisms by which the activity of these phosphatases is regulated. Our proposed studies will provide unique insights into the physiologic significance of the in vivo interactions between class IA PI3K and phosphatases in regulating growth and survival in SC/Ps.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075816-06
Application #
7894787
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Thomas, John
Project Start
2009-07-06
Project End
2011-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
6
Fiscal Year
2010
Total Cost
$426,677
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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:
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
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
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
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
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
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
Wen, Qiang; Goldenson, Benjamin; Silver, Serena J et al. (2012) Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL. Cell 150:575-89
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

Showing the most recent 10 out of 29 publications