Project 457143

Myeloproliferative neoplasms (MPNs) are a group of blood cancers/leukemias in which there is overproduction of one or more types of blood cells and affect ~5/100,000 persons. Polycythemia vera and essential thrombocythemia are MPNs characterized by elevated red blood cells and platelets, respectively, while myelofibrosis is a more aggressive subtype demonstrated by anemia, spleen enlargement, and bone marrow fibrosis. MPNs also exhibit a propensity for transformation to secondary acute myeloid leukemia (sAML), for which the prognosis is dismal (median survival < 6 months). Despite vigorous research, therapies capable of reliably halting or preventing MPN disease progression remain elusive. Thus, there is a pressing need to understand the mechanisms underlying this transformation process, which could translate to therapies capable of preventing and/or treating disease progression. We have identified elevated expression of DUSP6, a cancer growth promoter, in cells from sAML patients, suggesting it may drive disease progression. I propose to better define its role and those of downstream effectors with goals of targeting these candidates therapeutically. First, I will assess consequences of both elevated DUSP6 expression and gene knockout in mouse cancers models by measuring hallmarks of disease in the development of bone marrow fibrosis, blood cancer counts, and survival outcomes. Second, elevated expression of downstream effector RSK1 is also associated with poorer survival in AML patients. I aim to repurpose a clinical-grade RSK1 inhibitor that is currently being evaluated in clinical trials for solid tumors to treat these blood cancers. Following, I will study inhibitor efficacy in suppressing cancer across leukemia mouse models and patient samples. Collectively, the proposed studies will provide clarity in disease development and progression of MPN to AML and elucidate new therapeutic treatments for patients with blood cancers with a goal of a clinical trial.