1. Tumor-associated antigen PRAME exhibits dualistic functions that are targetable in diffuse large B cell lymphoma
- Author
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Takata, Katsuyoshi, Chong, Lauren C., Ennishi, Daisuke, Aoki, Tomohiro, Li, Michael Yu, Thakur, Avinash, Healy, Shannon, Vigano, 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, Adele, Kishida, Makoto, Rai, Shinya, Zhang, Allen W., Bashashati, Ali, Saberi, Saeed, DAntonio, Gianluca, Nelson, Brad H., Shah, Sohrab P., Hoodless, Pamela A., Melnick, Ari M., Gascoyne, Randy D., Connors, Joseph M., Scheinberg, David A., Beguelin, Wendy, Scott, David W., and Steidl, Christian
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Oncology, Experimental ,Gene mutations -- Research ,Immune response -- Genetic aspects ,Non-Hodgkin's lymphomas -- Genetic aspects -- Care and treatment ,Tumor antigens -- Genetic aspects ,Cancer -- Research ,Health care industry - 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., Introduction The current treatment standard of combined immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has achieved significant improvement in patient outcomes in diffuse large B cell lymphoma (DLBCL) [...]
- Published
- 2022
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