Abstract
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.
Keywords:
CBFb-SMMHC; CBFbeta; MYC; Runx1; acute myeloid leukemia; chromatin; enhancer.
Published by Elsevier Inc.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis* / drug effects
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Azepines / pharmacology
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Azepines / therapeutic use
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Benzimidazoles / pharmacology
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Benzimidazoles / therapeutic use
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Cell Line, Tumor
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Chromatin / metabolism*
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Chromosomal Proteins, Non-Histone / chemistry
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Chromosomal Proteins, Non-Histone / metabolism
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Chromosome Inversion / drug effects
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Core Binding Factor Alpha 2 Subunit / chemistry
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Core Binding Factor Alpha 2 Subunit / metabolism
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DNA / chemistry
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DNA / metabolism
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DNA Helicases / metabolism
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Disease Models, Animal
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Humans
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Kaplan-Meier Estimate
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Leukemia, Myeloid, Acute / drug therapy
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Leukemia, Myeloid, Acute / mortality
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Leukemia, Myeloid, Acute / pathology
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Mice
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Mice, Inbred C57BL
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Nuclear Proteins / metabolism
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Oncogene Proteins, Fusion / antagonists & inhibitors*
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Oncogene Proteins, Fusion / metabolism
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Polycomb Repressive Complex 1 / metabolism
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Promoter Regions, Genetic
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Protein Binding
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism*
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Transcription Factors / chemistry
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Transcription Factors / metabolism
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Triazoles / pharmacology
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Triazoles / therapeutic use
Substances
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(+)-JQ1 compound
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2,2'-(5,5'-((oxybis(ethane-2,1-diyl))bis(oxy))bis(pyridine-5,2-diyl))bis(6-(trifluoromethoxy)-1H-benzo(d)imidazole)
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Azepines
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Benzimidazoles
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CBFbeta-MYH11 fusion protein
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Chromatin
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Chromosomal Proteins, Non-Histone
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Core Binding Factor Alpha 2 Subunit
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Nuclear Proteins
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Oncogene Proteins, Fusion
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Proto-Oncogene Proteins c-myc
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SWI-SNF-B chromatin-remodeling complex
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Transcription Factors
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Triazoles
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DNA
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Polycomb Repressive Complex 1
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RNF2 protein, human
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SMARCA4 protein, human
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DNA Helicases