An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia Academic Article uri icon

Overview

MeSH Major

  • Amyloid Precursor Protein Secretases
  • Chromatin
  • Drug Resistance, Neoplasm
  • Enzyme Inhibitors
  • Epigenesis, Genetic
  • Nuclear Proteins
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
  • Transcription Factors

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 date

  • January 2014

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4086945

Digital Object Identifier (DOI)

  • 10.1038/ng.2913

PubMed ID

  • 24584072

Additional Document Info

start page

  • 364

end page

  • 70

volume

  • 46

number

  • 4