| First Author | Zhen T | Year | 2017 |
| Journal | Blood | Volume | 130 |
| Issue | 22 | Pages | 2431-2442 |
| PubMed ID | 29018080 | Mgi Jnum | J:251954 |
| Mgi Id | MGI:6106552 | Doi | 10.1182/blood-2017-04-780106 |
| Citation | Zhen T, et al. (2017) Chd7 deficiency delays leukemogenesis in mice induced by Cbfb-MYH11. Blood 130(22):2431-2442 |
| abstractText | 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 CBFbeta-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 Chd7(f)(/f)Mx1-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 Chd7(f/f)Mx1-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 Chd7(f/f)Mx1-CreCbfb(+/56M) mice, and genes associated with cell cycle, cell growth, and proliferation were differentially expressed between Chd7(f/f)Mx1-CreCbfb(+/56M) and Mx1-CreCbfb(+/56M) leukemic cells. In vitro studies showed that CHD7 interacted with CBFbeta-SMMHC through RUNX1 and that CHD7 enhanced transcriptional activity of RUNX1 and CBFbeta-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. |
