Sensitivity and engineered resistance of myeloid leukemia cells to BRD9 inhibition
| Autor: | Mark Pearson, Christopher R. Vakoc, Laetitia J. Martin, Manfred Koegl, Yutaka Suzuki, Thomas Gerstberger, Anja F. Hohmann, Jae Seok Roe, Jessica L. Minder, Steffen Steurer, Junwei Shi, Gerd Bader, Teresa Gottschamel, Darryl B. McConnell, Diane Thompson |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Models Molecular Myeloid Antineoplastic Agents Biology Article 03 medical and health sciences Mice Structure-Activity Relationship 0302 clinical medicine medicine Animals Humans Allele Molecular Biology Cell Engineering Alleles Cell Proliferation Dose-Response Relationship Drug Molecular Structure Cell growth Myeloid leukemia Cell Differentiation Cell Biology medicine.disease Molecular biology 3. Good health Bromodomain Leukemia Leukemia Myeloid Acute 030104 developmental biology medicine.anatomical_structure Cell culture Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Drug Screening Assays Antitumor Chemical genetics Transcription Factors |
| Zdroj: | Nature chemical biology |
| ISSN: | 1552-4469 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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