Journal
NATURE GENETICS
Volume 46, Issue 4, Pages 364-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2913
Keywords
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Categories
Funding
- US National Institutes of Health (NIH) Training [5-T32-GM007748-33]
- Doris Duke Charitable Foundation [2006087]
- Fulbright Diabetes UK Fellowship [BDA 11/0004348]
- Broad Institute
- NIH/NIDDK [5U01DK085526]
- DK088389
- National Human Genome Research Institute (NHGRI) [U54HG003067]
- NIH [U01 DK085501, U01 DK085524, U01 DK085545, U01 DK085584]
- Swedish Research Council [Dnr 521-2010-3490, Dnr 349-2006-237]
- European Research Council (ERC) [GENETARGET T2D, GA269045]
- ENGAGE [2007-201413]
- CEED3 [2008-223211]
- Sigrid Juselius Foundation and the Folkh lsan Research Foundation
- ERC [AdG 293574]
- Research Council of Norway [197064/V50]
- KG Jebsen Foundation
- University of Bergen
- Western Norway Health Authority
- Lundbeck Foundation
- Wellcome Trust [WT098017, WT064890, WT090532]
- Uppsala University
- Uppsala University Hospital
- Swedish Research Council
- Swedish Heart- Lung Foundation
- Academy of Finland [124243]
- Finnish Heart Foundation
- Finnish Diabetes Foundation, Tekes [1510/31/06]
- Commission of the European Community
- Commission of the European Community [HEALTH-F2-2007-201681]
- Ministry of Education and Culture of Finland
- European Commission Framework Programme 6 Integrated Project (EXGENESIS) [LSHM-CT-2004-005272]
- City of Kuopio and Social Insurance Institution of Finland
- The Academy of Finland [139635]
- Finnish Foundation for Cardiovascular Disease
- Wellcome Trust grants [WT098017, WT064890, WT090532, WT090367, WT098381]
- National Heart, Lung, and Blood Institute
- National Institute on Minority Health and Health Disparities [N01 HC-95170N01, HC-95171N01, HC-95172]
- European Union Seventh Framework Programme, DIAPREPP
- Swedish Child Diabetes Foundation
- US National Institutes of Health (NIH) [HL007574- 30]
- St. Baldrick's fellowship
- US NIH T32 training [CA130807, HL007627]
- American Cancer Society [125087-PF-13247-01-LIB]
- National Human Genome Research Institute [ENCODE U54 HG004570]
- NIH Common Fund for Epigenomics [U01 ES017155]
- NIH/NCI [CA096899, 5P01 CA109901-10]
- Howard Hughes Medical Institute
- Starr Cancer Consortium
- The Leukemia & Lymphoma Society Specialized Center of Research Program
- [R01DK062370]
- [R01DK072193]
- [Z01HG000024]
- [102318]
- [123885]
- [U01-DK085545]
Ask authors/readers for more resources
The identification of activating NOTCH1 mutations in T cell acute lymphoblastic leukemia (T-ALL) led to clinical testing of g-secretase inhibitors (GSIs) that prevent NOTCH1 activation1-4. However, responses to these inhibitors have been transient5, 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.
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