An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia
| Autor: | Matthew J. Cotton, Shawn M. Gillespie, Michael J. Kluk, Mohit Jain, Bradley E. Bernstein, Dale L. Greiner, Daniel S. Pearson, Michael A. Brehm, Serena J. Silver, Manching Ku, Jens G. Lohr, Andrew L. Kung, Federica Piccioni, Alejandro Gutierrez, Daniel Fernandez, Jiang Zhu, Kimberly Stegmaier, Christopher J. Ott, Kaylyn E. Williamson, Hongfang Wang, David E. Root, Michelle A. Kelliher, Jon C. Aster, James E. Bradner, Justine E. Roderick, Birgit Knoechel, Leonard D. Shultz |
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| Rok vydání: | 2014 |
| Předmět: |
Chromatin Immunoprecipitation
Indoles T cell medicine.medical_treatment Cell Cycle Proteins Enzyme-Linked Immunosorbent Assay Drug resistance Biology Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Real-Time Polymerase Chain Reaction Article Epigenesis Genetic Targeted therapy Histones Mice Cell Line Tumor hemic and lymphatic diseases Genetics medicine Animals Humans Epigenetics Enzyme Inhibitors Receptor Notch1 Regulation of gene expression Nuclear Proteins Azepines Triazoles Flow Cytometry Chromatin Gene Expression Regulation Neoplastic medicine.anatomical_structure Drug Resistance Neoplasm Cell culture Immunology Amyloid Precursor Protein Secretases Signal transduction Signal Transduction Transcription Factors |
| Zdroj: | Nature Genetics. 46:364-370 |
| ISSN: | 1546-1718 1061-4036 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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