The Journal of Clinical Investigation (May 2022)

Tumor-associated antigen PRAME exhibits dualistic functions that are targetable in diffuse large B cell lymphoma

  • Katsuyoshi Takata,
  • Lauren C. Chong,
  • Daisuke Ennishi,
  • Tomohiro Aoki,
  • Michael Yu Li,
  • Avinash Thakur,
  • Shannon Healy,
  • Elena Viganò,
  • Tao Dao,
  • Daniel Kwon,
  • Gerben Duns,
  • Julie S. Nielsen,
  • Susana Ben-Neriah,
  • Ethan Tse,
  • Stacy S. Hung,
  • Merrill Boyle,
  • Sung Soo Mun,
  • Christopher M. Bourne,
  • Bruce Woolcock,
  • Adèle Telenius,
  • Makoto Kishida,
  • Shinya Rai,
  • Allen W. Zhang,
  • Ali Bashashati,
  • Saeed Saberi,
  • Gianluca D’Antonio,
  • Brad H. Nelson,
  • Sohrab P. Shah,
  • Pamela A. Hoodless,
  • Ari M. Melnick,
  • Randy D. Gascoyne,
  • Joseph M. Connors,
  • David A. Scheinberg,
  • Wendy Béguelin,
  • David W. Scott,
  • Christian Steidl

Journal volume & issue
Vol. 132, no. 10

Abstract

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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.

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