Elucidating the Role of Mutated ASXL1 in Myeloproliferative Neoplasms

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Myeloproliferative neoplasms summarize certain types of bone marrow cancer, with the clonal expansion of at least one cell type of the myeloid lineage as a defining feature. Somatic, acquired mutations in JAK2, CALR or MPL have been identified as disease driver mutations. In myeloproliferative neoplasms, mutations in the additional sex combs-like protein 1 (ASXL1) gene often co-occur with the canonical driver mutations in hematopoietic stem cells. Importantly, co-occurrence of ASXL1 mutation adversely impacts prognosis and promotes transformation to a more aggressive disease (i.e. bone marrow fibrosis or acute leukemia). ASXL1 is an epigenetic regulator, controlling both transcriptional activation and repression. Different studies have identified several epigenetic changes in ASXL1 mutant models, but data on how ASXL1 mutation accelerates myeloproliferative disease in the context of the respective disease-initiating driver mutations are sparse. The research presented here therefore aims at identifying the mechanisms underlying the adverse impact of mutated ASXL1 on mutant CALR-mediated myeloproliferative neoplasms by generating ASXL1/CALR double mutant mice. I will investigate cell-intrinsic effects which drive leukemic transformation, and cell-extrinsic effects that promote myelofibrosis. In particular, RNA sequencing, novel epigenetic approaches and imaging techniques will be used to analyze effects of ASXL1/CALR mutation in hematopoietic stem cells and in the bone marrow microenvironment.