TY - JOUR
T1 - Sensitivity and engineered resistance of myeloid leukemia cells to BRD9 inhibition
AU - Hohmann, Anja F.
AU - Martin, Laetitia J.
AU - Minder, Jessica L.
AU - Roe, Jae Seok
AU - Shi, Junwei
AU - Steurer, Steffen
AU - Bader, Gerd
AU - McConnell, Darryl
AU - Pearson, Mark
AU - Gerstberger, Thomas
AU - Gottschamel, Teresa
AU - Thompson, Diane
AU - Suzuki, Yutaka
AU - Koegl, Manfred
AU - Vakoc, Christopher R.
N1 - Funding Information:
National Institutes of Health grant NCI RO1 CA174793.
Publisher Copyright:
© 2016 Nature America, Inc. All rights reserved.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84976874620&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84976874620&partnerID=8YFLogxK
U2 - 10.1038/nchembio.2115
DO - 10.1038/nchembio.2115
M3 - Article
C2 - 27376689
AN - SCOPUS:84976874620
SN - 1552-4450
VL - 12
SP - 672
EP - 679
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 9
ER -
