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.

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: 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.

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.