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CHD7 deficiency delays leukemogenesis in mice induced by CBFB-MYH11

Tao Zhen, Erika Kwon, Ling Zhao, Jingmei Hsu, R. Katherine Hyde, Ying Lu, Lemlem Alemu, Nancy A. Speck and P. Paul Liu

Key points

  • CHD7 interacts with CBFβ-SMMHC through RUNX1 and modulates their gene expression regulation.

  • CHD7 is important for CBFB-MYH11 leukemogenesis in the mouse model.

Abstract

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. Previous studies showed that the interaction between CBFβ-SMMHC (encoded by CBFB-MYH11) 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 CBFB-MYH11 induced leukemogenesis. To test this hypothesis, we generated Chd7f/f, Mx1-Cre, Cbfb+/56M mice, which expressed the Cbfb-MYH11 fusion gene and deactivated Chd7 in hematopoietic cells upon inducing Cre with poly (I:C). The LK (Lin-/Sca1-/c-Kit+) population was significantly lower in Chd7f/f, Mx1-Cre, Cbfb+/56M mice than that in Mx1-Cre, Cbfb+/56M mice. In addition, there were fewer BrdU+ cells in the LK population in Chd7f/f, Mx1-Cre, Cbfb+/56M mice, and genes associated with cell cycle, cell growth and proliferation were differentially expressed between Chd7f/f, Mx1-Cre, Cbfb+/56M and Mx1-Cre, Cbfb+/56M leukemic cells. In vitro studies showed that CHD7 interacted with CBFβ-SMMHC through RUNX1 and that CHD7 enhanced RUNX1 and CBFβ-SMMHC's transcriptional activity on Csf1r, a RUNX1 target gene. Moreover, RNA-seq of c-Kit+ cells showed that CHD7 functioned mostly through altering the expression of RUNX1 target genes. Most importantly, Chd7 deficiency delayed Cbfb-MYH11 induced leukemia in both primary and transplanted mice. These data indicate that Chd7 is important for Cbfb-MYH11 induced leukemogenesis by facilitating RUNX1 regulation of transcription and cellular proliferation.

  • Submitted April 19, 2017.
  • Accepted September 19, 2017.