4 years ago

CHD7 deficiency delays leukemogenesis in mice induced by CBFB-MYH11.

Hyde, Liu, Speck, Alemu, Lu, Zhao, Hsu, Kwon, Zhen
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 Chd7(f/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 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 LK population in Chd7(f/f) , Mx1-Cre, Cbfb(+/56M) mice, and genes associated with cell cycle, cell growth and proliferation were differentially expressed between Chd7(f/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.

Publisher URL: http://doi.org/10.1182/blood-2017-04-780106

DOI: 10.1182/blood-2017-04-780106

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.