CBFβ-SMMHC inhibition triggers apoptosis by disrupting MYC chromatin dynamics in acute myeloid leukemia
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...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
June 28, 2018
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| In: |
Cell
Year: 2018, Volume: 174, Issue: 1, Pages: 172-186, e1-e21 |
| ISSN: | 1097-4172 |
| DOI: | 10.1016/j.cell.2018.05.048 |
| Online Access: | Verlag, Volltext: https://doi.org/10.1016/j.cell.2018.05.048 Verlag: http://www.sciencedirect.com/science/article/pii/S0092867418307098 
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| Author Notes: | John Anto Pulikkan, Mahesh Hegde, Hafiz Mohd Ahmad, Houda Belaghzal, Anuradha Illendula, Jun Yu, Kelsey O’Hagan, Jianhong Ou, Carsten Muller-Tidow, Scot A. Wolfe, Lihua Julie Zhu, Job Dekker, John Hackett Bushweller, Lucio Hernán Castilla |
| Summary: | 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. |
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| Item Description: | corrected online: July 6, 2018 Gesehen am 15.05.2020 |
| Physical Description: | Online Resource |
| ISSN: | 1097-4172 |
| DOI: | 10.1016/j.cell.2018.05.048 |