An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia.
Document Type
Article
Publication Date
4-2014
JAX Source
Nat Genet 2014 Apr; 46(4):364-70.
ISSN
1546-1718
PMID
24584072
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. Nat Genet 2014 Apr; 46(4):364-70.
Recommended Citation
Knoechel B,
Roderick J,
Williamson K,
Zhu J,
Lohr J,
Cotton M,
Gillespie S,
Fernandez D,
Ku M,
Wang H,
Piccioni F,
Silver S,
Jain M,
Pearson D,
Kluk M,
Ott C,
Shultz LD,
Brehm M,
Greiner D,
Gutierrez A,
Stegmaier K,
Kung A,
Root D,
Bradner J,
Aster J,
Kelliher M,
Bernstein B.
An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nat Genet 2014 Apr; 46(4):364-70.