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

   

Authors:	Takata, K.; Chong, L. C.; Ennishi, D.; Aoki, T.; Li, M. Y.; Thakur, A.; Healy, S.; Viganò, E.; Dao, T.; Kwon, D.; Duns, G.; Nielsen, J. S.; Ben-Neriah, S.; Tse, E.; Hung, S. S.; Boyle, M.; Mun, S. S.; Bourne, C. M.; Woolcock, B.; Telenius, A.; Kishida, M.; Rai, S.; Zhang, A. W.; Bashashati, A.; Saberi, S.; D'Antonio, G.; Nelson, B. H.; Shah, S. P.; Hoodless, P. A.; Melnick, A. M.; Gascoyne, R. D.; Connors, J. M.; Scheinberg, D. A.; Béguelin, W.; Scott, D. W.; Steidl, C.
Article 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.
Keywords:	chemotherapy; rituximab; microenvironment; lung-cancer; t-cells; acute lymphoblastic-leukemia; generation; ezh2; regulatory; open-label; germinal center formation
Journal Title:	Journal of Clinical Investigation
Volume:	132
Issue:	10
ISSN:	0021-9738
Publisher:	American Society for Clinical Investigation
Date Published:	2022-05-16
Start Page:	e145343
Language:	English
ACCESSION:	WOS:000800763100005
DOI:	10.1172/jci145343
PROVIDER:	wos
PMCID:	PMC9106353
PUBMED:	35380993
Notes:	Article -- 145343 -- Source: Wos

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