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. (September 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) (Public Dataset)
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 Cancer Center Program > Gene Regulation and Cell Proliferation CSHL labs > Vakoc lab School of Biological Sciences > Publications CSHL Cancer Center Program > Cancer Genetics and Genomics Program |
| Depositing User: | Matt Covey |
| Date: | September 2016 |
| Date Deposited: | 06 Jul 2016 20:25 |
| Last Modified: | 05 Nov 2020 16:51 |
| PMCID: | PMC4990482 |
| Related URLs: | |
| Dataset ID: | |
| URI: | https://repository.cshl.edu/id/eprint/32953 |
Actions (login required)
 |
Administrator's edit/view item |