CBFβ-SMMHC Inhibition Triggers Apoptosis by Disrupting MYC Chromatin Dynamics in Acute Myeloid Leukemia. Cell 2018 Jun 28;174(1):172-186.e21
Date
06/30/2018Pubmed ID
29958106Pubmed Central ID
PMC6211564DOI
10.1016/j.cell.2018.05.048Scopus ID
2-s2.0-85048726457 (requires institutional sign-in at Scopus site) 60 CitationsAbstract
The fusion oncoprotein CBFβ-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 CBFβ-SMMHC maintains cell viability by neutralizing RUNX1-mediated repression of MYC expression. Upon pharmacologic inhibition of the CBFβ-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 CBFβ-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 CBFβ-SMMHC drives leukemia maintenance and suggests that inhibitors targeting chromatin activity may prove effective in inv(16) leukemia therapy.
Author List
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 LHAuthor
John A. Pulikkan PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
Azepines
Benzimidazoles
Cell Line, Tumor
Chromatin
Chromosomal Proteins, Non-Histone
Chromosome Inversion
Core Binding Factor Alpha 2 Subunit
DNA
DNA Helicases
Disease Models, Animal
Humans
Kaplan-Meier Estimate
Leukemia, Myeloid, Acute
Mice
Mice, Inbred C57BL
Nuclear Proteins
Oncogene Proteins, Fusion
Polycomb Repressive Complex 1
Promoter Regions, Genetic
Protein Binding
Proto-Oncogene Proteins c-myc
Transcription Factors
Triazoles