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Chd7 deficiency delays leukemogenesis in mice induced by Cbfb-MYH11

Tao Zhen, Erika M. 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, which generates a CBFB-MYH11 fusion gene. Previous studies showed that the interaction between CBFβ-smooth muscle myosin heavy chain (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/fMx1-CreCbfb+/56M mice, which expressed the Cbfb-MYH11 fusion gene and deactivated Chd7 in hematopoietic cells upon inducing Cre with polyinosinic-polycytidylic acid. The LinSca1c-Kit+ (LK) population was significantly lower in Chd7f/fMx1-CreCbfb+/56M mice than in Mx1-CreCbfb+/56M mice. In addition, there were fewer 5-bromo-2′-deoxyuridine–positive cells in the LK population in Chd7f/fMx1-CreCbfb+/56M mice, and genes associated with cell cycle, cell growth, and proliferation were differentially expressed between Chd7f/fMx1-CreCbfb+/56M and Mx1-CreCbfb+/56M 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 Csf1r, 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, 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.
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