Journal
CELL
Volume 174, Issue 1, Pages 172-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2018.05.048
Keywords
-
Categories
Funding
- NIH [R01 CA204979, R01 CA140398]
- Leukemia & Lymphoma Society [6463-15]
- ASH Bridge
- UMASS Cancer Center
- Alex's Lemonade Stand Foundation
- Lauri Strauss Leukemia Foundation
Ask authors/readers for more resources
The fusion oncoprotein CBF beta-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 CBF beta-SMMHC maintains cell viability by neutralizing RUNX1-mediated repression of MYC expression. Upon pharmacologic inhibition of the CBF beta-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 CBF beta-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 CBF beta-SMMHC drives leukemia maintenance and suggests that inhibitors targeting chromatin activity may prove effective in inv(16) leukemia therapy.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available