A CHAF1B-dependent molecular switch in hematopoiesis and leukemia pathogenesis

CHAF1B is the p60 subunit of the chromatin assembly factor (CAF1) complex, which is responsible for assembly of H3.1/H4 heterodimers at the replication fork during S phase. Here we report that CHAF1B is required for normal hematopoiesis while its overexpression promotes leukemia. CHAF1B has a pro-leukemia effect by binding chromatin at discrete sites and interfering with occupancy of transcription factors that promote myeloid differentiation, such as CEBPA. Reducing Chaf1b activity by either heterozygous deletion or overexpression of a CAF1 dominant negative allele was sufficient to suppress leukemogenesis in vivo without impairing normal hematopoiesis. Examination of the function of CHAF1B in maintaining undifferentiated state of leukemic cells. We used Chaf1b-floxed MLL-AF9 leukemic cell clones which were transduced with CreERT2. Knockout was induced by treatment with B-estradiol, and cells were lysed 48 hours after induction for analysis. Floxed cells expressing CreERT2 treated with EtOH were used as clonal controls.