Sensitivity and engineered resistance of myeloid leukemia cells to BRD9 inhibition

Hohmann, A. F., Martin, L. J., Minder, J. L., Roe, J. S., Shi, J., Steurer, S., Bader, G., McConnell, D., Pearson, M., Gerstberger, T., Gottschamel, T., Thompson, D., Suzuki, Y., Koegl, M., Vakoc, C. R. (2016) Sensitivity and engineered resistance of myeloid leukemia cells to BRD9 inhibition. Nat Chem Biol, 12 (9). pp. 672-9. ISSN 1552-4469 (Electronic)1552-4450 (Linking)

URL: http://www.ncbi.nlm.nih.gov/pubmed/27376689
DOI: 10.1038/nchembio.2115

Abstract

Here we show that acute myeloid leukemia (AML) cells require the BRD9 subunit of the SWI-SNF chromatin-remodeling complex to sustain MYC transcription, rapid cell proliferation and a block in differentiation. Based on these observations, we derived small-molecule inhibitors of the BRD9 bromodomain that selectively suppress the proliferation of mouse and human AML cell lines. To establish these effects as on-target, we engineered a bromodomain-swap allele of BRD9 that retains functionality despite a radically altered bromodomain pocket. Expression of this allele in AML cells conferrs resistance to the antiproliferative effects of our compound series, thus establishing BRD9 as the relevant cellular target. Furthermore, we used an analogous domain-swap strategy to generate an inhibitor-resistant allele of EZH2. To our knowledge, our study provides the first evidence for a role of BRD9 in cancer and reveals a simple genetic strategy for constructing resistance alleles to demonstrate on-target activity of chemical probes in cells.

Item Type: Paper
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transcription
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > BET bromodomain coactivator protein
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > BET bromodomain coactivator protein > Brd9
CSHL Authors:
Communities: CSHL labs > Vakoc lab
Watson School > Publications
Depositing User: Matt Covey
Date Deposited: 06 Jul 2016 20:25
Last Modified: 07 Sep 2017 14:29
PMCID: PMC4990482
Related URLs:
Dataset ID:
URI: http://repository.cshl.edu/id/eprint/32953

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