title: 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.affiliation: 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].
authors.forename: Birgit
authors.initials: B
authors.lastname: Knoechel
authors.affiliation: 1] Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA. [2].
authors.forename: Justine E
authors.initials: JE
authors.lastname: Roderick
authors.affiliation: 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.
authors.forename: Kaylyn E
authors.initials: KE
authors.lastname: Williamson
authors.affiliation: 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.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
authors.affiliation: 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Jens G
authors.initials: JG
authors.lastname: Lohr
authors.affiliation: 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.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Cotton
authors.affiliation: 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.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Gillespie
authors.affiliation: 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Biostatistics Graduate Program, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fernandez
authors.affiliation: 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.
authors.forename: Manching
authors.initials: M
authors.lastname: Ku
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Hongfang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Federica
authors.initials: F
authors.lastname: Piccioni
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Serena J
authors.initials: SJ
authors.lastname: Silver
authors.affiliation: 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.
authors.forename: Mohit
authors.initials: M
authors.lastname: Jain
authors.affiliation: 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.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pearson
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kluk
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ott
authors.affiliation: Jackson Laboratory, Bar Harbor, Maine, USA.
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Brehm
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Dale L
authors.initials: DL
authors.lastname: Greiner
authors.affiliation: 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.
authors.forename: Alejandro
authors.identifier: 0000000202499007
authors.initials: A
authors.lastname: Gutierrez
authors.affiliation: 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.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Stegmaier
authors.affiliation: 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.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.affiliation: 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.affiliation: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Kelliher
authors.affiliation: 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.
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Bernstein
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D044127:Epigenesis, Genetic / Q000235:genetics*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D007211:Indoles; D051379:Mice; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology; D000092468:Bromodomain Containing Proteins
chemical_list: D053829:Amyloid Precursor Protein Secretases; D001381:Azepines; D018797:Cell Cycle Proteins; D002843:Chromatin; D004791:Enzyme Inhibitors; D006657:Histones; D007211:Indoles; D009687:Nuclear Proteins; D051881:Receptor, Notch1; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C497761:NOTCH1 protein, human; C007293:DAPI