Abstract PR14: Polycomb repressive complex 2 inactivation induces primary chemotherapy resistance in T-ALL by upregulating the TRAP1 mitochondrial chaperone

Abstract

Abstract The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of the outcome of cytotoxic chemotherapy for cancer. To fully exploit this finding, it will be important to understand the molecular genetic contexts responsible for the relative mitochondrial priming of chemotherapy-sensitive versus resistant cell populations. 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) and consequent downstream upregulation of the TRAP1 gene, which encodes a mitochondrial chaperone protein of the HSP90 family. In clinical samples from 47 T-ALL patients, we found that loss-of-function mutations in any of three core components of PRC2 (EZH2, EED or SUZ12) were associated with resistance to mitochondrial apoptosis, as assessed by BH3 profiling (P = 0.015). In human T-ALL cells, PRC2 depletion induced resistance to mitochondrial apoptosis induction, as assessed by caspase 3/7 activation or annexin V/PI staining, in response to multiple antileukemic drugs with distinct mechanisms of action, including dexamethasone, doxorubicin, vincristine, and asparaginase (P < 0.01). In mouse immature T-cell progenitors, haploinsufficiency for the PRC2 components Ezh2 or Eed was sufficient to induce resistance to mitochondrial apoptosis, as assessed by BH3 profiling analysis (P ≤ 0.01). PRC2 is a histone-modifying complex whose activity is strongly associated with transcriptional repression. We found that PRC2 represses transcription of TRAP1, a nuclearly encoded, mitochondrially localized chaperone of the HSP90 family. Importantly, TRAP1 overexpression was necessary to induce resistance to chemotherapy-induced apoptosis downstream of PRC2 inactivation (P < 0.001), while pharmacologic inhibition of TRAP1 synergized with antileukemic drugs in PRC2-deficient leukemic cells. These findings demonstrate the importance of relative mitochondrial apoptotic priming as a prognostic factor in T-ALL, and implicate mitochondrial chaperone function as a molecular determinant of response to cancer chemotherapy, suggesting a rationale for targeted therapeutic intervention. This abstract is also being presented as Poster 07. Citation Format: Ingrid Aries, Triona Ni Chonghaile, Salmaan Karim, Sebastian Balbach, Melissa Burns, Gayle Pouliot, Stevenson Kristen, Donna Neuberg, Meenakshi Devidas, Loh Mignon, Stephen Hunger, Stuart Winter, David Teachey, Karen Rabin, Kimberly Dunsmore, Brent Wood, Lewis Silverman, Stephen Sallan, Peter Van Vlierberghe, Stuart H. Orkin, Anthony G. Letai, Alejandro Gutierrez. Polycomb repressive complex 2 inactivation induces primary chemotherapy resistance in T-ALL by upregulating the TRAP1 mitochondrial chaperone [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr PR14.