deficiency delays leukemogenesis in mice induced by .

Inversion of chromosome 16 is a consistent finding in patients with acute myeloid leukemia subtype M4 with eosinophilia, which generates a fusion gene. Previous studies showed that the interaction between CBFβ-smooth muscle myosin heavy chain (SMMHC; encoded by ) and RUNX1 plays a critical role in the pathogenesis of this leukemia. Recently, it was shown that chromodomain helicase DNA-binding protein-7 (CHD7) interacts with RUNX1 and suppresses RUNX1-induced expansion of hematopoietic stem and progenitor cells. These results suggest that CHD7 is also critical for induced leukemogenesis. To test this hypothesis, we generated mice, which expressed the fusion gene and deactivated in hematopoietic cells upon inducing with polyinosinic-polycytidylic acid. The LinSca1c-Kit (LK) population was significantly lower in mice than in mice. In addition, there were fewer 5-bromo-2'-deoxyuridine-positive cells in the LK population in mice, and genes associated with cell cycle, cell growth, and proliferation were differentially expressed between and leukemic cells. In vitro studies showed that CHD7 interacted with CBFβ-SMMHC through RUNX1 and that CHD7 enhanced transcriptional activity of RUNX1 and CBFβ-SMMHC on , a RUNX1 target gene. Moreover, RNA sequencing of c-Kit cells showed that CHD7 functions mostly through altering the expression of RUNX1 target genes. Most importantly, deficiency delayed induced leukemia in both primary and transplanted mice. These data indicate that is important for induced leukemogenesis by facilitating RUNX1 regulation of transcription and cellular proliferation.