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Granulocyte colony-stimulating factor (G-CSF) is widely used to enhance myeloid recovery after chemotherapy and to mobilize hematopoietic stem cells (HSCs) for transplantation. Unfortunately, through the course of chemotherapy, cancer patients can acquire leukemogenic mutations that cause therapy-related myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). This raises the question of whether therapeutic G-CSF might potentiate therapy-related MDS/AML by disproportionately stimulating mutant HSCs and other myeloid progenitors. A common mutation in therapy-related MDS/AML involves chromosome 7 deletions that inactivate many tumor suppressor genes, including KMT2C. Here, we show that Kmt2cdeletions hypersensitize murine HSCs and myeloid progenitors to G-CSF, as evidenced by increased HSC mobilization and enhanced granulocyte production from granulocyte-monocyte progenitors (GMPs). Furthermore, Kmt2cattenuates the G-CSF response independently from its SET methyltransferase function. Altogether, the data raise concerns that monosomy 7 can hypersensitize progenitors to G-CSF, such that clinical use of G-CSF may amplify the risk of therapy-related MDS/AML.

The myeloid tumor suppressor KMT2Cis recurrently deleted in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), particularly therapy-related MDS/AML (t-MDS/t-AML), as part of larger chromosome 7 deletions. Here, we show that KMT2Cdeletions convey a selective advantage to hematopoietic stem cells (HSCs) after chemotherapy treatment that may precipitate t-MDS/t-AML. Kmt2cdeletions markedly enhance murine HSC self-renewal capacity without altering proliferation rates. Haploid Kmt2cdeletions convey a selective advantage only when HSCs are driven into cycle by a strong proliferative stimulus, such as chemotherapy. Cycling Kmt2c-deficient HSCs fail to differentiate appropriately, particularly in response to interleukin-1. Kmt2cdeletions mitigate histone methylation/acetylation changes that accrue as HSCs cycle after chemotherapy, and they impair enhancer recruitment during HSC differentiation. These findings help explain why Kmt2cdeletions are more common in t-MDS/t-AML than in de novoAML or clonal hematopoiesis: they selectively protect cycling HSCs from differentiation without inducing HSC proliferation themselves.