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Blood. 2017 Nov 30;130(22):2431-2442. doi: 10.1182/blood-2017-04-780106. Epub 2017 Oct 10.

Chd7 deficiency delays leukemogenesis in mice induced by Cbfb-MYH11.

Author information

1
Oncogenesis and Development Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
2
Division of Hematology/Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA.
3
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE.
4
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD; and.
5
Abramson Family Cancer Research Institute and.
6
Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA.

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 Lin-Sca1-c-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.

PMID:
29018080
PMCID:
PMC5709785
DOI:
10.1182/blood-2017-04-780106
[Indexed for MEDLINE]
Free PMC Article

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