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

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

doi:10.1038/ng.2913

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.

Authors

Birgit Knoechel¹, Justine E Roderick², Kaylyn E Williamson³, Jiang Zhu³, Jens G Lohr⁴, Matthew J Cotton³, Shawn M Gillespie³, Daniel Fernandez⁵, Manching Ku⁶, Hongfang Wang⁷, Federica Piccioni⁸, Serena J Silver⁸, Mohit Jain⁹, Daniel Pearson¹⁰, Michael J Kluk⁷, Christopher J Ott¹¹, Leonard D Shultz¹², Michael A Brehm¹³, Dale L Greiner¹³, Alejandro Gutierrez¹⁴, Kimberly Stegmaier¹⁴, Andrew L Kung¹⁴, David E Root⁸, James E Bradner⁴, Jon C Aster⁷, Michelle A Kelliher¹⁵, Bradley E Bernstein³

Affiliations

¹ 1] Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [4] Division of Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [5].
² 1] Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA. [2].
³ 1] Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3] Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts, USA. [4] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
⁴ 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
⁵ 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Biostatistics Graduate Program, Harvard University, Cambridge, Massachusetts, USA.
⁶ 1] Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3] Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁷ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁸ Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
⁹ 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. [3] Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹⁰ 1] Division of Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Biological and Biomedical Sciences Graduate Program, Harvard Medical School, Boston, Massachusetts, USA.
¹¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
¹² Jackson Laboratory, Bar Harbor, Maine, USA.
¹³ Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
¹⁴ 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Division of Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
¹⁵ Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

PMID: 24584072
PMCID: PMC4086945
DOI: 10.1038/ng.2913

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

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding