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). 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.
Regulation of Hematopoietic Stem Cells and Leukemic Cells by the Microenvironment
Hematopoietic cells are supported by multiple cell types within the bone marrow microenvironment, collectively termed the "niche". There is known to be bi-directional crosstalk between hematopoietic stem cells and their niche, which controls HSC quiescence, self-renewal, and lineage fate decisions. This crosstalk also affects niche cell function and organization. We are using multiple model systems to investigate the mechanisms though which the niche regulates HSC numbers and HSC fate decisions (DOI: 10.1038/s41586-025-09462-5). This includes an ongoing effort to identify and characterize novel niche factors that regulate HSC and leukemic cell function at steady state and under stress conditions.
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 (doi.org/10.1172/jci.insight.125832). We are studying how deletion of PI3K will impact normal HSC function, including self-renewal, proliferation, and differentiation along different blood lineages. We have found that deletion of all three Class IA PI3K isoforms impairs HSC differentiation, and causes a phenotype resembling myelodysplastic syndrome (MDS) through dysregulation of autophagy (doi: 10.1126/sciadv.ade8222) .
Roles of PI3 kinase 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. We previously 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 (doi: 10.1172/JCI69927). We found that leukemic stem cells also depend upon PI3K isoforms, but that targeting PI3K in leukemia can lead to non-genetic resistance mechanisms (doi: https://doi.org/10.1101/2025.07.11.663968). Our ongoing work is focused on identifying these adaptive resistance mechanisms and on understanding how PI3K inactivation in leukemia can affect immune recognition and elimination of leukemic cells.