|Publication Type||Journal Article|
|Year of Publication||2014|
|Authors||Knoechel, 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|
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.