Haploid Kmt2c Deletions Enhance Hematopoietic Stem Cell Mobilization in Response to Granulocyte-Colony Stimulating Factor

KMT2C is one of several tumor suppressor genes deleted in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) as part of larger chromosome 7q deletions. These deletions are particularly common in therapy-related MDS/AML, raising the question of whether loss of one or more 7q genes conveys a selective advantage to hematopoietic stem cells (HSCs) in the setting of chemotherapy-induced stress. We recently showed that haploid Kmt2c deletions do indeed enhance HSC self-renewal capacity. However, the deletions do not drive HSCs into cycle; instead, a proliferative stress such as chemotherapy is required to create a context in which Kmt2c deletion convey a selective advantage. We have also identified a mechanism, to explain this phenotype. Kmt2c encodes MLL3, a SET domain protein that binds enhancers and facilitates transcription. We have shown that Kmt2c/MLL3 deletions impairs enhancer recruitment during HSC differentiation, therefore blunting HSC commitment.