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Nat Genet 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
JournalNat Genet
Volume46
Issue4
Pages364-70
Date Published2014 Apr
ISSN1546-1718
KeywordsAmyloid Precursor Protein Secretases, Animals, Azepines, Cell Line, Tumor, Chromatin, Chromatin Immunoprecipitation, Drug Resistance, Neoplasm, Enzyme Inhibitors, Enzyme-Linked Immunosorbent Assay, Epigenesis, Genetic, Flow Cytometry, Gene Expression Regulation, Neoplastic, Histones, Humans, Indoles, Mice, Nuclear Proteins, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Real-Time Polymerase Chain Reaction, Receptor, Notch1, Signal Transduction, Transcription Factors, Triazoles
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.

URLhttp://dx.doi.org/10.1038/ng.2913
DOI10.1038/ng.2913
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24584072?dopt=Abstract

Alternate JournalNat. Genet.
PubMed ID24584072
PubMed Central IDPMC4086945
Grant ListU54 HG006991 / HG / NHGRI NIH HHS / United States
T32 HL007574 / HL / NHLBI NIH HHS / United States
CA096899 / CA / NCI NIH HHS / United States
P01 CA109901 / CA / NCI NIH HHS / United States
R01 CA096899 / CA / NCI NIH HHS / United States
T32 HL007627 / HL / NHLBI NIH HHS / United States
P30 CA034196 / CA / NCI NIH HHS / United States
5P01 CA109901-10 / CA / NCI NIH HHS / United States
U54 HG004570 / HG / NHGRI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
T32 CA130807 / CA / NCI NIH HHS / United States
U01 ES017155 / ES / NIEHS NIH HHS / United States