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

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 w...

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Detalles Bibliográficos
Autores principales: Takata, Katsuyoshi, Chong, Lauren C., Ennishi, Daisuke, Aoki, Tomohiro, Li, Michael Yu, Thakur, Avinash, Healy, Shannon, Viganò, Elena, Dao, Tao, Kwon, Daniel, Duns, Gerben, Nielsen, Julie S., Ben-Neriah, Susana, Tse, Ethan, Hung, Stacy S., Boyle, Merrill, Mun, Sung Soo, Bourne, Christopher M., Woolcock, Bruce, Telenius, Adèle, Kishida, Makoto, Rai, Shinya, Zhang, Allen W., Bashashati, Ali, Saberi, Saeed, D’Antonio, Gianluca, Nelson, Brad H., Shah, Sohrab P., Hoodless, Pamela A., Melnick, Ari M., Gascoyne, Randy D., Connors, Joseph M., Scheinberg, David A., Béguelin, Wendy, Scott, David W., Steidl, Christian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
Materias:
Research Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9106353/
https://www.ncbi.nlm.nih.gov/pubmed/35380993
http://dx.doi.org/10.1172/JCI145343
Descripción
Sumario: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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