Letter to the EditorImmunology Open Access | 10.1172/JCI160983
1Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic.
2Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
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Published July 15, 2022 - More info
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.
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
Katsuyoshi Takata, Christian Steidl
Takata et al. (1) reported that patients with diffuse large B cell lymphoma (DLBCL) relatively frequently (13% of patients) harbor a deletion at the 22q11.22 locus that involves the PRAME gene, and that PRAME loss is associated with poor outcomes and leads to cytotoxic T cell immune escape. The authors comment that “deletions...were located close to the Igλ gene.” I would like to bring to the attention of the authors and readers that the PRAME gene and neighboring ZNF280A, ZNF280B, and GGTLC2 genes are located between variable (V) subgenes for the immunoglobulin lambda (Igλ) light chain (Figure 1). The PRAME deletion is inevitable when a B lymphocyte (normal or malignant) rearranges the Igλ locus and utilizes one of the many V subgenes located more distantly from the J-C region. It is known that approximately 30% to 40% of B lymphocytes express Igλ (~60%–70% express Igκ, since this locus for the Ig light chain is rearranged before Igλ). Therefore, it is not surprising that the loss of PRAME has been previously noted in multiple B cell malignancies, especially chronic lymphocytic leukemia (2–4). Takata et al. (1) observed that patients with PRAME deletions more often have an Igλ rearrangement, but they also report cases of DLBCL with a PRAME deletion and rearranged Igκ. However, it is not clear if in such cases the Igκ rearrangement was productive and what the status of the Igλ locus was. A defective allelic exclusion process might lead to Igκ and Igλ expression in one B cell. PRAME deletion associates with prognosis in DLBCL (1), but it should be considered that such a deletion could also be viewed as a surrogate marker for the use of one of the distal Igλ V subgenes (Figure 1), and it is known that Igλ usage associates with prognosis and B cell receptor (BCR) pathway deregulation in B cell malignancies (5).
Schematic of the human Igλ locus organization and the location of the PRAME gene.
In summary, loss of PRAME is an expected phenomena in a portion of normal or malignant B cells with Igλ rearrangement. It remains puzzling why in evolution PRAME has been placed between Igλ subgenes and why its expression is activated in DLBCL.
Conflict of interest: The author has declared that no conflict of interest exists.
Address correspondence to: Marek Mraz, Associate Professor of Oncology, Central European Institute of Technology, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic. Phone: 420.549498143; Email: firstname.lastname@example.org.
Reference information: J Clin Invest. 2022;132(14):e160983. https://doi.org/10.1172/JCI160983.
See the related article at Tumor-associated antigen PRAME exhibits dualistic functions that are targetable in diffuse large B cell lymphoma .
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