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

doi:10.1172/JCI145343

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 TeleniusMakoto 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^*

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

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.

Original language	English
Article number	e145343
Journal	Journal of Clinical Investigation
Volume	132
Issue number	10
DOIs	https://doi.org/10.1172/JCI145343
State	Published - 2022/05/16

ASJC Scopus subject areas

General Medicine

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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., ... Steidl, C. (2022). Tumor-associated antigen PRAME exhibits dualistic functions that are targetable in diffuse large B cell lymphoma. Journal of Clinical Investigation, 132(10), Article e145343. https://doi.org/10.1172/JCI145343

@article{8285b278446446abbc2f22a22dd3e856,

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.",

author = "Katsuyoshi Takata and Chong, {Lauren C.} and Daisuke Ennishi and Tomohiro Aoki and Li, {Michael Yu} and Avinash Thakur and Shannon Healy and Elena Vigan{\`o} and Tao Dao and Daniel Kwon and Gerben Duns and Nielsen, {Julie S.} and Susana Ben-Neriah and Ethan Tse and Hung, {Stacy S.} and Merrill Boyle and Mun, {Sung Soo} and Bourne, {Christopher M.} and Bruce Woolcock and Ad{\`e}le Telenius and Makoto Kishida and Shinya Rai and Zhang, {Allen W.} and Ali Bashashati and Saeed Saberi and Gianluca D'Antonio and Nelson, {Brad H.} and Shah, {Sohrab P.} and Hoodless, {Pamela A.} and Melnick, {Ari M.} and Gascoyne, {Randy D.} and Connors, {Joseph M.} and Scheinberg, {David A.} and Wendy B{\'e}guelin and Scott, {David W.} and Christian Steidl",

note = "Publisher Copyright: {\textcopyright} 2022, Takata et al.",

year = "2022",

month = may,

day = "16",

doi = "10.1172/JCI145343",

language = "英語",

volume = "132",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

number = "10",

}

Takata, K, Chong, LC, Ennishi, D, Aoki, T, Li, MY, Thakur, A, Healy, S, Viganò, E, Dao, T, Kwon, D, Duns, G, Nielsen, JS, Ben-Neriah, S, Tse, E, Hung, SS, Boyle, M, Mun, SS, Bourne, CM, Woolcock, B, Telenius, A, Kishida, M, Rai, S, Zhang, AW, Bashashati, A, Saberi, S, D'Antonio, G, Nelson, BH, Shah, SP, Hoodless, PA, Melnick, AM, Gascoyne, RD, Connors, JM, Scheinberg, DA, Béguelin, W, Scott, DW & Steidl, C 2022, 'Tumor-associated antigen PRAME exhibits dualistic functions that are targetable in diffuse large B cell lymphoma', Journal of Clinical Investigation, vol. 132, no. 10, e145343. https://doi.org/10.1172/JCI145343

TY - JOUR

T1 - Tumor-associated antigen PRAME exhibits dualistic functions that are targetable in diffuse large B cell lymphoma

AU - Takata, Katsuyoshi

AU - Chong, Lauren C.

AU - Ennishi, Daisuke

AU - Aoki, Tomohiro

AU - Li, Michael Yu

AU - Thakur, Avinash

AU - Healy, Shannon

AU - Viganò, Elena

AU - Dao, Tao

AU - Kwon, Daniel

AU - Duns, Gerben

AU - Nielsen, Julie S.

AU - Ben-Neriah, Susana

AU - Tse, Ethan

AU - Hung, Stacy S.

AU - Boyle, Merrill

AU - Mun, Sung Soo

AU - Bourne, Christopher M.

AU - Woolcock, Bruce

AU - Telenius, Adèle

AU - Kishida, Makoto

AU - Rai, Shinya

AU - Zhang, Allen W.

AU - Bashashati, Ali

AU - Saberi, Saeed

AU - D'Antonio, Gianluca

AU - Nelson, Brad H.

AU - Shah, Sohrab P.

AU - Hoodless, Pamela A.

AU - Melnick, Ari M.

AU - Gascoyne, Randy D.

AU - Connors, Joseph M.

AU - Scheinberg, David A.

AU - Béguelin, Wendy

AU - Scott, David W.

AU - Steidl, Christian

PY - 2022/5/16

Y1 - 2022/5/16

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85130112592&partnerID=8YFLogxK

U2 - 10.1172/JCI145343

DO - 10.1172/JCI145343

M3 - 学術論文

C2 - 35380993

AN - SCOPUS:85130112592

SN - 0021-9738

VL - 132

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 10

M1 - e145343

ER -

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

Abstract

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