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J Exp Med. 2018 Dec 3;215(12):3094-3114. doi: 10.1084/jem.20180570. Epub 2018 Nov 7.

PRC2 loss induces chemoresistance by repressing apoptosis in T cell acute lymphoblastic leukemia.

Author information

1
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
3
Deparment of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
4
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
5
Department of Pediatric Oncology, University Hospital Muenster, Muenster, Germany.
6
Center for Medical Genetics, Ghent University, Ghent, Belgium.
7
Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
8
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA.
9
Department of Biostatistics, University of Florida, Gainesville, FL.
10
Department of Pediatrics, University of California San Francisco, San Francisco, CA.
11
Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA.
12
Division of Pediatric Hematology/Oncology, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX.
13
Cancer and Blood Disorders Department, Children's Minnesota, Minneapolis, MN.
14
Department of Pediatrics, Carilion Children's, Roanoke, VA.
15
Department of Laboratory Medicine, University of Washington, Seattle, WA.
16
Howard Hughes Medical Institute, Boston, MA.
17
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA alejandro.gutierrez@childrens.harvard.edu.

Abstract

The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. Fully exploiting this finding will require unraveling the molecular genetics underlying phenotypic variability in mitochondrial priming. Here, we report that mitochondrial apoptosis resistance in T cell acute lymphoblastic leukemia (T-ALL) is mediated by inactivation of polycomb repressive complex 2 (PRC2). In T-ALL clinical specimens, loss-of-function mutations of PRC2 core components (EZH2, EED, or SUZ12) were associated with mitochondrial apoptosis resistance. In T-ALL cells, PRC2 depletion induced resistance to apoptosis induction by multiple chemotherapeutics with distinct mechanisms of action. PRC2 loss induced apoptosis resistance via transcriptional up-regulation of the LIM domain transcription factor CRIP2 and downstream up-regulation of the mitochondrial chaperone TRAP1 These findings demonstrate the importance of mitochondrial apoptotic priming as a prognostic factor in T-ALL and implicate mitochondrial chaperone function as a molecular determinant of chemotherapy response.

PMID:
30404791
PMCID:
PMC6279404
[Available on 2019-06-03]
DOI:
10.1084/jem.20180570

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