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- Title
An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia.
- Authors
Knoechel, Birgit; Roderick, Justine E; Williamson, Kaylyn E; Zhu, Jiang; Lohr, Jens G; Cotton, Matthew J; Gillespie, Shawn M; Fernandez, Daniel; Ku, Manching; Wang, Hongfang; Piccioni, Federica; Silver, Serena J; Jain, Mohit; Pearson, Daniel; Kluk, Michael J; Ott, Christopher J; Shultz, Leonard D; Brehm, Michael A; Greiner, Dale L; Gutierrez, Alejandro; Stegmaier, Kimberly; Kung, Andrew L; Root, David E; Bradner, James E; Aster, Jon C; Kelliher, Michelle A; Bernstein, Bradley E
- Abstract
The identification of activating NOTCH1 mutations in T cell acute lymphoblastic leukemia (T-ALL) led to clinical testing of γ-secretase inhibitors (GSIs) that prevent NOTCH1 activation. However, responses to these inhibitors have been transient, suggesting that resistance limits their clinical efficacy. Here we modeled T-ALL resistance, identifying GSI-tolerant 'persister' cells that expand in the absence of NOTCH1 signaling. Rare persisters are already present in naive T-ALL populations, and the reversibility of their phenotype suggests an epigenetic mechanism. Relative to GSI-sensitive cells, persister cells activate distinct signaling and transcriptional programs and exhibit chromatin compaction. A knockdown screen identified chromatin regulators essential for persister viability, including BRD4. BRD4 binds enhancers near critical T-ALL genes, including MYC and BCL2. The BRD4 inhibitor JQ1 downregulates expression of these targets and induces growth arrest and apoptosis in persister cells, at doses well tolerated by GSI-sensitive cells. Consistently, the GSI-JQ1 combination was found to be effective against primary human leukemias in vivo. Our findings establish a role for epigenetic heterogeneity in leukemia resistance that may be addressed by incorporating epigenetic modulators in combination therapy.
- Publication
Nature genetics, 2014, Vol 46, Issue 4, p364
- ISSN
1546-1718
- Publication type
Journal Article
- DOI
10.1038/ng.2913