Sensitivity and engineered resistance of myeloid leukemia cells to BRD9 inhibition

Anja F. Hohmann, Laetitia J. Martin, Jessica L. Minder, Jae Seok Roe, Junwei Shi, Steffen Steurer, Gerd Bader, Darryl McConnell, Mark Pearson, Thomas Gerstberger, Teresa Gottschamel, Diane Thompson, Yutaka Suzuki, Manfred Koegl, Christopher R. Vakoc

Research output: Contribution to journalArticle

65 Citations (Scopus)

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 confers 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.

Original languageEnglish
Pages (from-to)672-679
Number of pages8
JournalNature Chemical Biology
Volume12
Issue number9
DOIs
Publication statusPublished - 2016 Sep 1

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Sensitivity and engineered resistance of myeloid leukemia cells to BRD9 inhibition'. Together they form a unique fingerprint.

  • Cite this

    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. Nature Chemical Biology, 12(9), 672-679. https://doi.org/10.1038/nchembio.2115