The Roles of Signaling Pathways in Adult Blood Development and Leukemia

The Gritsman 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. We are interested in how signaling pathways affect the self-renewal and differentiation of HSCs and malignant or pre-malignant stem cells in myeloid malignancies, such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN).

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 recently reported that PI3K isoforms play important redundant roles during the hematopoietic stress response, such as after chemotherapy. However, deletion of all 3 Class IA PI3K isoforms leads to a phenotype with impaired HSC differentiation, resembling myelodysplastic syndrome (MDS). We are studying how deletion of PI3K will impact normal HSC function, including self-renewal, proliferation, and differentiation along different blood lineages by affecting processes such as autophagy and epigenetic regulation in HSCs.

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. Furthermore, we 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.

RON Kinase in Myeloproliferative Neoplasms

The myeloproliferative neoplasms (MPNs) are a group of diseases that are caused by kinase mutations in HSCs, which lead to uncontrolled proliferation of myeloid cells. The Philadelphia chromosome-negative MPNs are characterized by mutations in the JAK/STAT signaling pathway, and respond to JAK inhibitors, but resistance often develops. We recently discovered that the receptor Tyrosine kinase RON can physically interact with JAK2 in MPN cells, leading to potentiation of JAK/STAT signaling in resistant cells. Furthermore, we found that pharmacologic or genetic inactivation of RON can inhibit proliferation of MPN cells and re-sensitize resistant cells to JAK inhibitors.

Member of the Cancer Dormancy and Tumor Microenvironment Institute 

 The Gritsman lab’s research interests include the contributions of signaling pathways to leukemic and pre-leukemic stem cell dormancy in minimal residual disease, which includes mechanisms of immune evasion. Furthermore, the Gritsman lab is interested in the roles of inflammatory signaling pathways and of the local microenvironment in bone marrow fibrosis, and in the evolution of myeloid neoplasms from the pre-malignant to malignant state. Our major goals are to identify opportunities for therapeutic targeting to prevent the transition from the pre-leukemic state to leukemia, or to eliminate minimal residual disease to prevent relapse.

Ames, K.,  Kaur, I., Shi, Y., Tong, M., Sinclair, T., Hemmati, S., Glushakow-Smith, S.G., Tein,  E., Gurska, L., Steidl, U., Dubin, R., Shan, J., Montagna, C., Pradhan, K., Verma, A., and Gritsman, K., Deletion of PI3-Kinase Promotes Myelodysplasia Through Dysregulation of Autophagy in Hematopoietic Stem Cells, Science Advances 2023. doi: 10.1126/sciadv.ade8222, PMID: 36812307

Folgado Marco, V., Ames, K., Chuen, J., Gritsman, K. & Baker, N., Haploinsufficiency of the essential gene RpS12 causes defects in erythropoiesis and hematopoietic stem cell maintenance,  eLife 2023 Jun 5;12:e69322. doi: 10.7554/eLife.69322. PMID: 37272618

Gurska, L.M., Okabe, R., Schurer, A., Tong, M.M., Soto, M., Choi, D., Ames, K., Glushakow-Smith, S., Montoya, A., Tein, E., Miles, L.A., Cheng, H., Hankey-Giblin, P., Levine, R.L., Goel, S., Halmos, B., and Gritsman, K. Crizotinib has Preclinical Efficacy in Philadelphia-negative Myeloproliferative Neoplasms, Clinical Cancer Research 2022 Dec 20:CCR-22-1763. doi: 10.1158/1078-0432.CCR-22-1763. PMID: 36537918

Gurska, L., Ames, K., and Gritsman, K, Signaling Pathways in Leukemic Stem Cells, In: Zhang H., Li S. (eds) Leukemia Stem Cells in Hematologic Malignancies. Advances in Experimental Medicine and Biology, vol 1143. Springer, Singapore, July 24, 2019, doi: https://doi.org/10.1007/978-981-13-7342-8_1; PMID: 31338813, PMCID: PMC7249489

Hemmati, S., Sinclair, T., Tong, M., Bartholdy, B., Okabe, R.O., Ames, K., Ostrodka, L., Haque, T., Kaur, I., Mills, T. S., Agarwal, A., Pietras, E.M., Zhao, J.J., Roberts, T.M., and Gritsman, K., PI3 kinase alpha and delta promote hematopoietic stem cell activation, JCI Insight 2019 doi.org/10.1172/jci.insight.125832

Mitchell, K., Barreyro, L., Todorova, T., Taylor, S., Antony-Debre, I., Narayanagari, S., Carvajal, L., Leite, J., Piperdi, Z., Pendurti, G., Mantzaris, I., Paietta, E., Verma, A., Gritsman, K., and Steidl, U. IL1RAP potentiates multiple oncogenic signaling pathways in AML, Journal of Experimental Medicine. 2018 May 17. doi: 10.1084/jem.20180147, PMID: 29773641

Hemmati, S., Haque, T., and Gritsman, K, Inflammatory Signaling Pathways in Pre-leukemic and Leukemic Stem Cells, Frontiers in Oncology 2017 Nov 13;7:265. doi: 10.3389/fonc.2017.00265

Bhagat, T.D., Chen, S., Bartenstein, M., Barlowe, A.T., Von Ahrens, D., Choudhary, G.S., Tivnan, P., Amin, E., Marcondes, M., Sanders, M.A., Hoogenboezem, R.M., Kambhampati, S., Ramanchandra, N., Mantzaris, I., Sukrithan, V., Laurence, R., Lopez, R. Bhagat, P., Giricz, O., Sohal, D., Wickrema, A., Yeung, C., Gritsman, K., Aplan, P., Hochedlinger, K., Yu, Y., Pradhan, K., Zhang, J., Greally, J.M., Mukherjee, S., Pellagatti, A., Boultwood, J., Will, B., Steidl, U., Raaijmakers, M.H.G.P., Deeg, H.J., Kharas, M.G. and Verma, A. Epigenetically Aberrant Stroma in MDS Propagates Disease Via Wnt/b-Catenin Activation, 2017 Cancer Research 2017 Jul 6. pii: canres.0282.2017. doi: 10.1158/0008-5472

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

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., 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, K. 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, K. Constitutively Active AKT Depletes Hematopoietic Stem Cells and Induces Leukemia in Mice. Blood 2010; 115(7): 140615 http://www.bloodjournal.org/content/115/7/1406