Tumor-associated antigen PRAME exhibits dualistic functions that are targetable in diffuse large B cell lymphoma
Katsuyoshi Takata, … , David W. Scott, Christian Steidl
Katsuyoshi Takata, … , David W. Scott, Christian Steidl
Published April 5, 2022
Citation Information: J Clin Invest. 2022;132(10):e145343. https://doi.org/10.1172/JCI145343.
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Research Article Hematology Oncology Article has an altmetric score of 4

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.

Authors

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

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Figure 3

EZH2 Y641 hotspot mutations are significantly enriched in PRAME-negative cases and functionally suppress PRAME expression via promoter binding.

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EZH2 Y641 hotspot mutations are significantly enriched in PRAME-negativ...
(A) Forest plot shows association with somatic status between PRAME IHC-positive and IHC-negative samples. Red bars indicate statistical significance. The frequency of gene mutations is shown on the right and based on PRAME IHC status. (B) Volcano plot of downregulated and upregulated genes in EZH2-mutated versus WT samples (adjusted P < 0.05). (C) H3K27me3 ChIP quantitative PCR analysis on PRAME promoter region between EZH2-WT cell lines (HT, SU-DHL-8, DOHH-2, and HBL-1) and mutated cell lines (Karpas-422, SU-DHL-10, DB, WSU-DLCL2, SU-DHL-4, and SU-DHL-6). Data were normalized by ACTB (Bonferroni’s multiple-comparison test, mean ± SEM, **P < 0.01).