CHD7 Deficiency Inhibits CBFB-MYH11 -Induced Leukemogenesis

Inversion of chromosome 16 is a consistent finding in patients with acute myeloid leukemia subtype M4 with eosinophilia (AML M4Eo), which generates a CBFB-MYH11 fusion gene. Mechanistic studies showed that the interaction between CBFbeta-SMMHC (encoded by CBFB-MYH11) and RUNX1 plays a critical role in the leukemogenesis of this kind of 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 also plays a role in CBFB-MYH11 induced leukemogenesis. To test this hypothesis, we crossed Cre-based conditional Chd7 knockout mice (Chd7^f/f) with Cre-based conditional Cbfb-MYH11 knockin mice (Cbfb^+/56M) to generate Chd7^f/f, Mx1-Cre, Cbfb^+/56M mice, which express Cbfbeta-SMMHC but not CHD7 after poly I:C treatment to induce Cre expression. Three weeks after poly I:C treatment, the Lin- and the Lin-/Sca1-/c-Kit+ (LK) progenitor cell populations were significantly lower in Chd7^f/f, Mx1-Cre, Cbfb^+/56M mice than that in Mx1-Cre, Cbfb^+/56M mice. In addition, there were fewer BrdU+ cells in the Lin- and LK populations in the Chd7^f/f, Mx1-Cre, Cbfb^+/56M mice. Importantly, Chd7^f/f, Mx1-Cre, Cbfb^+/56M mice developed leukemia with a much longer latency than the Mx1-Cre, Cbfb^+/56M mice. Secondary transplantation assay demostrated that spleen cells isolated from Chd7^f/f, Mx1-Cre, Cbfb^+/56M and Mx1-Cre, Cbfb^+/56M leukemic mice were transplantable, but recipients that received spleen cells from Chd7^f/f, Mx1-Cre, Cbfb^+/56M leukemic mice had a longer latency than those who received cells from Mx1-Cre, Cbfb^+/56M mice. The above results suggest that CHD7 deficiency slows leukemia initiation and development by inhibiting the proliferation ability of the Lin- and LK populations. Further mechanistic studies showed that CHD7 interacted with RUNX1 but not CBFbeta-SMMHC by co-Immunoprecipitation and immunofluorescence staining, suggesting that CHD7 is a partner of the RUNX1-CBFbeta-SMMHC transcription complex. In vitro luciferase assay showed that CHD7 enhanced RUNX1 and CBFbeta-SMMHC's transcriptional activity on M-CSFR, a RUNX1 target gene. These data indicate that CHD7 is important for Cbfb-MYH11 induced leukemogenesis by facilitating RUNX1 regulation of transcription and cellular proliferation.