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CBFbeta-SMMHC Inhibition Triggers Apoptosis by Disrupting MYC Chromatin Dynamics in Acute Myeloid Leukemia

Pulikkan, John A.
Hegde, Mahesh
Ahmad, Hafiz Mohd
Belaghzal, Houda
Illendula, Anuradha
Yu, Jun
O'Hagan, Kelsey
Ou, Jianhong
Muller-Tidow, Carsten
Wolfe, Scot A.
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Abstract

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.

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Cell. 2018 Jun 28;174(1):172-186.e21. doi: 10.1016/j.cell.2018.05.048. Link to article on publisher's site

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10.1016/j.cell.2018.05.048
PubMed ID
29958106
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