@article{af5c32bc694a4dd5b8a313e78d4bfd2d,
title = "Tumor-associated antigen PRAME exhibits dualistic functions that are targetable in diffuse large B cell lymphoma",
abstract = "PRAME is a prominent member of the cancer testis antigen family of proteins, which triggers autologous T cell-mediated immune responses. Integrative genomic analysis in diffuse large B cell lymphoma (DLBCL) uncovered recurrent and highly focal deletions of 22q11.22, including the PRAME gene, which were associated with poor outcome. PRAME-deleted tumors showed cytotoxic T cell immune escape and were associated with cold tumor microenvironments. In addition, PRAME downmodulation was strongly associated with somatic EZH2 Y641 mutations in DLBCL. In turn, PRC2-regulated genes were repressed in isogenic PRAME-KO lymphoma cell lines, and PRAME was found to directly interact with EZH2 as a negative regulator. EZH2 inhibition with EPZ-6438 abrogated these extrinsic and intrinsic effects, leading to PRAME expression and microenvironment restoration in vivo. Our data highlight multiple functions of PRAME during lymphomagenesis and provide a preclinical rationale for synergistic therapies combining epigenetic reprogramming with PRAME-targeted therapies.",
author = "Katsuyoshi Takata and Chong, {Lauren C.} and Daisuke Ennishi and Tomohiro Aoki and Li, {Michael Yu} and Avinash Thakur and Shannon Healy and Elena Vigan{\`o} and Tao Dao and Daniel Kwon and Gerben Duns and Nielsen, {Julie S.} and Susana Ben-Neriah and Ethan Tse and Hung, {Stacy S.} and Merrill Boyle and Mun, {Sung Soo} and Bourne, {Christopher M.} and Bruce Woolcock and Ad{\`e}le Telenius and Makoto Kishida and Shinya Rai and Zhang, {Allen W.} and Ali Bashashati and Saeed Saberi and Gianluca D'Antonio and Nelson, {Brad H.} and Shah, {Sohrab P.} and Hoodless, {Pamela A.} and Melnick, {Ari M.} and Gascoyne, {Randy D.} and Connors, {Joseph M.} and Scheinberg, {David A.} and Wendy B{\'e}guelin and Scott, {David W.} and Christian Steidl",
note = "Funding Information: CS received program project grant funding from the Terry Fox Research Institute Program Project Grant (grant 1061), the Leukemia and Lymphoma Society of Canada, Genome Canada (grant 13124), Genome BC (grant 271LYM), and the BC Cancer Foundation. CS is supported by the Michael Smith Foundation for Health Research (Career Investigator Award). KT received a fellowship award from the Uehara Memorial Foundation. AT is supported by Canadian Institutes of Health Research grants (FRN-128092 and FRN-153006) awarded to PAH. This work was also supported by the Center for Coordination of Research Facilities, Niigata University. Funding Information: Conflict of interest: CS has performed consultancy for Seattle Genetics, Curis Inc., Roche, AbbVie, Juno Therapeutics, and Bayer and has received research funding from Bristol Myers Squibb and Trillium Therapeutics Inc. DAS is a consultant to Eureka Therapeutics. Memorial Sloan Kettering Cancer Center has filed for patent protection on behalf of DAS for materials discussed in the paper (US20180148503A1). Copyright: {\textcopyright} 2022, Takata et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. Submitted: October 26, 2020; Accepted: March 29, 2022; Published: May 16, 2022. Reference information: J Clin Invest. 2022;132(10):e145343. https://doi.org/10.1172/JCI145343. Publisher Copyright: {\textcopyright} 2022, Takata et al.",
year = "2022",
month = may,
day = "16",
doi = "10.1172/JCI145343",
language = "English",
volume = "132",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "10",
}
