CBFbeta-SMMHC Inhibition Triggers Apoptosis by Disrupting MYC Chromatin Dynamics in Acute Myeloid Leukemia
Department of Molecular, Cell and Cancer Biology; Program in Systems Biology; Department of Biochemistry and Molecular Pharmacology
Cancer Biology | Cell Biology | Molecular Biology | Neoplasms | Structural Biology | Systems Biology
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.
acute myeloid leukemia, Runx1, CBFbeta, CBFb-SMMHC, MYC, enhancer, chromatin
DOI of Published Version
Cell. 2018 Jun 28;174(1):172-186.e21. doi: 10.1016/j.cell.2018.05.048. Link to article on publisher's site
Pulikkan JA, Hegde M, Ahmad HM, Belaghzal H, Illendula A, Yu J, O'Hagan K, Ou J, Muller-Tidow C, Wolfe SA, Zhu LJ, Dekker J, Bushweller JH, Castilla LH. (2018). CBFbeta-SMMHC Inhibition Triggers Apoptosis by Disrupting MYC Chromatin Dynamics in Acute Myeloid Leukemia. Program in Systems Biology Publications. https://doi.org/10.1016/j.cell.2018.05.048. Retrieved from https://escholarship.umassmed.edu/sysbio_pubs/125