Interrogating the Role of ASXL1and JAK2mutations in Myeloproliferative Neoplasms Utilizing Human Pluripotent Stem Cells

JAK2V617F is the most frequent mutation found in myeloproliferative neoplasms (MPNs), with 50-60% of myelofibrosis (MF) patients harboring this mutation. Mutations in ASXL1often co-occur with JAK2V617F and are associated with decreased survival and increased risk of transformation to secondary acute myeloid leukemia. How mutant ASXL1contributes to the MPN disease phenotype and confers poor prognosis is not fully understood. Controversy remains as to whether ASXL1mutations found in patients confer a loss of function, gain of function, and/or dominant negative phenotype. Additionally, Asxl1mutation knock in mouse models present with a relatively modest phenotype, following a very long latency period. A human model system has the potential to provide a useful tool to understand how these mutations affect ASXL1 function. This project therefore seeks to uncover how expression of mutant JAK2in conjunction with mutant ASXL1influences hematopoietic output and proliferation, utilizing human pluripotent stem cells.