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Nature genetics DOI:10.1038/ng.2913

An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia.

Publication TypeJournal Article
Year of Publication2014
AuthorsKnoechel, B, Roderick, JE, Williamson, KE, Zhu, J, Lohr, JG, Cotton, MJ, Gillespie, SM, Fernandez, D, Ku, M, Wang, H, Piccioni, F, Silver, SJ, Jain, M, Pearson, D, Kluk, MJ, Ott, CJ, Shultz, LD, Brehm, MA, Greiner, DL, Gutierrez, A, Stegmaier, K, Kung, AL, Root, DE, Bradner, JE, Aster, JC, Kelliher, MA, Bernstein, BE
JournalNature genetics
Date Published2014/03/02

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.