Washington University in St. Louis
Project Term: July 1, 2023 - June 30, 2026
This research will investigate blood stem cell mutations associated with progression of myeloproliferative neoplasm (MPN) to secondary acute myeloid leukemia (sAML). Our preliminary data suggest that pre-leukemic cells with particular mutations may have a selective advantage in a background of certain MPN subtypes. We will confirm this by utilizing mouse models and both MPN and sAML primary patient samples. Ultimately, we will examine and test inhibition of mechanisms which drive MPN to sAML.
Myeloproliferative neoplasms (MPNs) are blood cancers driven by mutations acquired in hematopoietic stem cells (HSCs) characterized by the unregulated proliferation of one or more blood cell lineages. More than 300,000 patients are currently living with an MPN diagnosis in the United States. MPN often progresses from polycythemia vera (PV; excess erythrocytes), essential thrombocythemia (ET; excess platelets), or myelofibrosis (MF; bone marrow fibrosis) and transforms to secondary acute myeloid leukemia (sAML). Mutations in the JAK2 gene are often present at the MPN stage but can occasionally be absent at the sAML stage while other leukemic mutations arise and expand. In these rarer, understudied cases, there are very limited treatment options coupled with an average survival of less than six months. Clinical data suggests that the JAK2 mutant MPN to JAK2 wild-type sAML trajectory occurs more frequently in PV patients compared to other MPN subtypes. The mechanisms leading to this phenomenon are currently not understood. Thus, our understanding of how these mutations cooperate with MPN to drive the formation of leukemia is particularly important. We propose that MPN subtypes may exhibit properties which provide a selective advantage for certain clones with non JAK2 mutations to expand unchecked. Ultimately, this leads to sAML which arises independently of the MPN, and which lacks the JAK2 mutation. The specific aims for this project are to 1) determine if both JAK2 and non-JAK2 mutations exist in the same cell at any point in the transformation process, 2) discover if an MPN subtype provides a selective advantage to leukemic mutations, 3) elucidate the mechanism which drives clonal advantage effect, and 4) inhibit the mechanism to ablate the advantage for leukemic occurrence. The primary outcome of this study will be to examine clonal expansion rates in patients with chronic MPN and those with MPN to sAML transformation. We will determine which mutations outcompete others in this understudied cohort of cancer patients. The data will not only deliver lacking insight into biological mechanisms of MPN to sAML transformation, but it will also provide an understanding of how clones with diverse mutations arising from different subtypes of MPN interact and compete in an architecturally and clinically relevant patient-derived model. This study could lead to better clinical predictive tools, improved disease surveillance, and potential therapeutic targets.