| First Author | Pulikkan JA | Year | 2018 |
| Journal | Cell | Volume | 174 |
| Issue | 1 | Pages | 172-186.e21 |
| PubMed ID | 29958106 | Mgi Jnum | J:265661 |
| Mgi Id | MGI:6193254 | Doi | 10.1016/j.cell.2018.05.048 |
| Citation | Pulikkan JA, et al. (2018) CBFbeta-SMMHC Inhibition Triggers Apoptosis by Disrupting MYC Chromatin Dynamics in Acute Myeloid Leukemia. Cell 174(1):172-186.e21 |
| abstractText | The fusion oncoprotein CBFbeta-SMMHC, expressed in leukemia cases with chromosome 16 inversion, drives leukemia development and maintenance by altering the activity of the transcription factor RUNX1. Here, we demonstrate that CBFbeta-SMMHC maintains cell viability by neutralizing RUNX1-mediated repression of MYC expression. Upon pharmacologic inhibition of the CBFbeta-SMMHC/RUNX1 interaction, RUNX1 shows increased binding at three MYC distal enhancers, where it represses MYC expression by mediating the replacement of the SWI/SNF complex component BRG1 with the polycomb-repressive complex component RING1B, leading to apoptosis. Combining the CBFbeta-SMMHC inhibitor with the BET inhibitor JQ1 eliminates inv(16) leukemia in human cells and a mouse model. Enhancer-interaction analysis indicated that the three enhancers are physically connected with the MYC promoter, and genome-editing analysis demonstrated that they are functionally implicated in deregulation of MYC expression. This study reveals a mechanism whereby CBFbeta-SMMHC drives leukemia maintenance and suggests that inhibitors targeting chromatin activity may prove effective in inv(16) leukemia therapy. |
