The PI3 kinase Signaling Pathway in Adult Blood Development and Leukemia
My lab studies the signal transduction pathways that affect the early fate decisions of adult hematopoietic stem cells (HSCs) as they progress from an undifferentiated multipotent state to the generation of differentiated blood cells. When these early fate decisions go awry, this can lead to the formation of leukemia-initiating cells.
Roles of the PI3 kinase isoforms in adult blood development
PI3 kinase (PI3K) is a lipid kinase that is important for the regulation of metabolism, the cell cycle, apoptosis, and protein synthesis. In hematopoietic cells, there are four isoforms of the catalytic subunit of PI3K, each encoded by a separate gene. Emerging evidence suggests that these isoforms have unique functions in normal and cancer cells, but may substitute for each other in some contexts. We have generated a series of mouse knockout models that allow us to study the roles of each of these isoforms individually in adult hematopoiesis. For example, we have found that the p110alpha isoform is most important for red cell development, but is not required in normal blood stem cells. We have now also generated compound knockout mice to determine the redundant roles of the PI3K isoforms in blood development. We are studying how deletion of PI3K will impact normal HSC function, including self-renewal, proliferation, and differentiation along different blood lineages.
Roles of the PI3 kinase isoforms in leukemia
Acute myeloid leukemia (AML) is a genetically diverse disease, but activation of the PI3K pathway has been reported in up to 80% of cases. A subset of AML cell lines and AML patient samples respond to PI3K pathway inhibitors, but it is unclear how patients should be selected for potential response to these inhibitors. We found that RAS-mutated myeloid leukemias are particularly dependent on the p110alpha isoform of PI3K, and that pharmacologic inhibition of p110alpha can be used to treat both RAS-mutated cell lines and RAS-mutated leukemia in mice. Our future work will be focused on generating a more comprehensive understanding of the molecular determinants for PI3K dependence in hematologic malignancies. Furthermore, we plan to use cell lines, patient samples, and mouse models of leukemia to investigate the mechanisms of resistance to PI3K inhibition, with the goal of identifying new drug targets and designing new combination treatments for leukemia that incorporate PI3K inhibitors.
Yuzugullu, H., Baitsch, L., Von, T., Steiner, A., Tong, H., Ni, J., Clayton, L., Bronson, R., Roberts, T., Gritsman, K., and Zhao, J.J. A p110b-Rac signaling loop mediates Pten-loss-induced perturbation of hematopoiesis and leukemogenesis. Nature Communications October 7,2015, doi:10.1038/NCOMMS9501
Cheng, H., Zou, Y., Ross, J.S., Wang, K., Liu, X., Halmos, B., Ali, S.M., Liu, H., Verma, A., Montagna, C., Chachoua, A., Goel, S., Schwartz, E.L., Zhu, C., Shan, J., Yu, Y., Gritsman, K., Yelensky, R., Lipson, D, Otto, G., Hawryluk, M., Stephens, P.J., Miller, V.A., Piperdi, B., Perez-Soler, R., RICTOR amplification defines a novel subset of lung cancer patients who may benefit from treatment with mTOR1/2 inhibitors. Cancer Discovery Published OnlineFirst September 14, 2015; doi:10.1158/2159-8290.CD-14-0971
Pandolfi A, Stanley RF, Yu Y, Bartholdy B, Pendurti G, Gritsman K, Boultwood J, Chernoff J, Verma A, Steidl U. PAK1 is a Therapeutic Target in Acute Myeloid Leukemia and Myelodysplastic Syndrome. Blood. 2015 Jul 13. pii: blood-2014-12-618801.
Yoda, A., Adelmant, G., Tamburini, J., Chapuy, B., Shindoh, N., Yoda, Y., Weigert, O., Kopp, N., Wu, S-C., Kim, S., Liu, H., Tivey, T., Christie, A.L., Gritsman, K., Gotlib, J., Deininger, M., Turley, S., Tyner, J., Marto, J., Weinstock, D.M., and Lane, A.A. Mutations in G-protein beta subunits promote transformation and kinase inhibitor resistance Nature Medicine 2015 (1):71-5.
Gritsman, K.1, Yuzugullu, H., Von, T., Yan, H., Clayton, L., Fritsch, C., Maira, S.-M., Hollingworth, G., Choi, C., Khandan, T., Paktinat, M., Okabe, R.O., Roberts, T.M., and Zhao, J.J. Hematopoiesis and RAS-driven myeloid leukemia differentially require PI3K isoform p110alpha. Journal of Clinical Investigation 2014;124(4):1794–1809. http://www.jci.org/articles/view/69927
Kharas, M.G. and Gritsman, K1. Akt: A Double-Edged Sword for Hematopoietic Stem Cells. Cell Cycle 2010; Vol 9; Issue 7
Kharas, M.G., Okabe, R., Ganis, J.J., Gozo,M., Khandan,T., Paktinat, M., Gilliland, D.G., and Gritsman, K1. Constitutively Active AKT Depletes Hematopoietic Stem Cells and Induces Leukemia in Mice. Blood 2010; 115(7): 1406-15 http://www.bloodjournal.org/content/115/7/1406
Gritsman, K., Talbot, W.S., and Schier, A.F. Nodal signaling patterns the organizer. Development 2000;127(5): 921-932
Gritsman, K.2, Zhang, J.2, Cheng, S., Heckscher, E., Talbot, W.S., and Schier, A.F. The EGF-CFC Protein One-Eyed Pinhead is Essential for Nodal Signaling. Cell 1999; 97: 121-132
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Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
1300 Morris Park Avenue
Chanin Building, Room 410
Bronx, NY 10461