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

(2018) JOURNAL OF EXPERIMENTAL MEDICINE. 215(12). p.3094-3114
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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 mitochondria) 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, FED, 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.
Keywords
MITOCHONDRIAL PERMEABILITY TRANSITION, PROLIFERATIVE ACTIVITY, EZH2 CONTROLS, COMPLEX 2, MUTATIONS, THERAPY, RESISTANCE, ABNORMALITIES, TRANSCRIPTION, DISCOVERY

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Chicago
Ariës, Ingrid M, Kimberly Bodaar, Salmaan A Karim, Triona Ni Chonghaile, Laura Hinze, Melissa A Burns, Maren Pfirrmann, et al. 2018. “PRC2 Loss Induces Chemoresistance by Repressing Apoptosis in T Cell Acute Lymphoblastic Leukemia.” Journal of Experimental Medicine 215 (12): 3094–3114.
APA
Ariës, I. M., Bodaar, K., Karim, S. A., Chonghaile, T. N., Hinze, L., Burns, M. A., Pfirrmann, M., et al. (2018). PRC2 loss induces chemoresistance by repressing apoptosis in T cell acute lymphoblastic leukemia. JOURNAL OF EXPERIMENTAL MEDICINE, 215(12), 3094–3114.
Vancouver
1.
Ariës IM, Bodaar K, Karim SA, Chonghaile TN, Hinze L, Burns MA, et al. PRC2 loss induces chemoresistance by repressing apoptosis in T cell acute lymphoblastic leukemia. JOURNAL OF EXPERIMENTAL MEDICINE. 2018;215(12):3094–114.
MLA
Ariës, Ingrid M et al. “PRC2 Loss Induces Chemoresistance by Repressing Apoptosis in T Cell Acute Lymphoblastic Leukemia.” JOURNAL OF EXPERIMENTAL MEDICINE 215.12 (2018): 3094–3114. Print.
@article{8583150,
  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 mitochondria) 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, FED, 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.},
  author       = {Ari{\"e}s, Ingrid M and Bodaar, Kimberly and Karim, Salmaan A and Chonghaile, Triona Ni and Hinze, Laura and Burns, Melissa A and Pfirrmann, Maren and Degar, James and Landrigan, Jack T and Balbach, Sebastian and Peirs, Sofie and Menten, Bj{\"o}rn and Isenhart, Randi and Stevenson, Kristen E and Neuberg, Donna S and Devidas, Meenakshi and Loh, Mignon L and Hunger, Stephen P and Teachey, David T and Rabin, Karen R and Winter, Stuart S and Dunsmore, Kimberly P and Wood, Brent L and Silverman, Lewis B and Sallan, Stephen E and Van Vlierberghe, Pieter and Orkin, Stuart H and Knoechel, Birgit and Letai, Anthony G and Gutierrez, Alejandro},
  issn         = {0022-1007},
  journal      = {JOURNAL OF EXPERIMENTAL MEDICINE},
  language     = {eng},
  number       = {12},
  pages        = {3094--3114},
  title        = {PRC2 loss induces chemoresistance by repressing apoptosis in T cell acute lymphoblastic leukemia},
  url          = {http://dx.doi.org/10.1084/jem.20180570},
  volume       = {215},
  year         = {2018},
}

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