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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis*
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm*
  • Female
  • Gene Expression Regulation, Leukemic / drug effects
  • Humans
  • Male
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Polycomb Repressive Complex 2 / genetics
  • Polycomb Repressive Complex 2 / metabolism*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Transcription, Genetic / drug effects
  • Up-Regulation / drug effects


  • Antineoplastic Agents
  • Neoplasm Proteins
  • Polycomb Repressive Complex 2

Associated data

  • RefSeq/NM_003797
  • RefSeq/NM_004456