An Epigenetic Mechanism of Resistance to Targeted Therapy in T Cell Acute Lymphoblastic Leukemia

Nat Genet. 2014 Apr;46(4):364-70. doi: 10.1038/ng.2913. Epub 2014 Mar 2.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Animals
  • Azepines / pharmacology
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Chromatin / genetics*
  • Chromatin / 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
  • Gene Expression Regulation, Neoplastic / genetics
  • Histones / metabolism
  • Humans
  • Indoles
  • Mice
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Real-Time Polymerase Chain Reaction
  • Receptor, Notch1 / antagonists & inhibitors
  • Receptor, Notch1 / genetics
  • Signal Transduction / genetics
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Triazoles / pharmacology

Substances

  • (+)-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

Associated data

  • GEO/GSE54380