An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia.

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.

• Authors: Birgit Knoechel, Justine E Roderick, Kaylyn E Williamson, Jiang Zhu, Jens G Lohr, Matthew J Cotton, Shawn M Gillespie, Daniel Fernandez, Manching Ku, Hongfang Wang, Federica Piccioni, Serena J Silver, Mohit Jain, Daniel Pearson, Michael J Kluk, Christopher J Ott, Leonard D Shultz, Michael A Brehm, Dale L Greiner, Alejandro Gutierrez, Kimberly Stegmaier, Andrew L Kung, David E Root, James E Bradner, Jon C Aster, Michelle A Kelliher, Bradley E Bernstein
• Journal: Nature genetics (Nat Genet) Vol. 46 Issue 4 Pg. 364-70 (Apr 2014) ISSN: 1546-1718 [Electronic] United States
• PMID: 24584072 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• (+)-JQ1 compound
• Azepines
• BRD4 protein, human
• Cell Cycle Proteins
• Chromatin
• Enzyme Inhibitors
• Histones
• Indoles
• NOTCH1 protein, human
• Nuclear Proteins
• Receptor, Notch1
• Transcription Factors
• Triazoles
• DAPI
• Amyloid Precursor Protein Secretases

Topics

• Amyloid Precursor Protein Secretases (antagonists & inhibitors)
• Animals
• Azepines (pharmacology)
• Cell Cycle Proteins
• Cell Line, Tumor
• Chromatin (genetics, metabolism)
• Chromatin Immunoprecipitation
• Drug Resistance, Neoplasm (genetics)
• Enzyme Inhibitors (therapeutic use)
• Enzyme-Linked Immunosorbent Assay
• Epigenesis, Genetic (genetics)
• Flow Cytometry
• Gene Expression Regulation, Neoplastic (drug effects, genetics)
• Histones (metabolism)
• Humans
• Indoles
• Mice
• Nuclear Proteins (antagonists & inhibitors, genetics, metabolism)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics)
• Real-Time Polymerase Chain Reaction
• Receptor, Notch1 (antagonists & inhibitors, genetics)
• Signal Transduction (genetics)
• Transcription Factors (antagonists & inhibitors, genetics, metabolism)
• Triazoles (pharmacology)