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Cell. 2018 Jun 28;174(1):172-186.e21. doi: 10.1016/j.cell.2018.05.048.

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

Author information

1
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
2
Howard Hughes Medical Institute, Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA.
3
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA.
4
Department of Medicine, Hematology, Oncology, and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany.
5
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA. Electronic address: lucio.castilla@umassmed.edu.

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

PMID:
29958106
PMCID:
PMC6211564
DOI:
10.1016/j.cell.2018.05.048
[Indexed for MEDLINE]
Free PMC Article

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