The authors reply:
We thank Dr. Mraz for insightful comments that provide additional context to the findings in our study, in particular bringing to the forefront studies in other B cell malignancies including chronic lymphocytic leukemia (CLL) (1). As pointed out in the Letter by Dr. Mraz and discussed in our manuscript, PRAME deletions were significantly associated with Ig-λ rearrangements, and this finding is consistent with a mechanism in which PRAME deletions can occur in the context of rearrangement of variable (V) gene loci on chromosome 22 in a subset of patients (2). For this reason, we studied frequencies and treatment outcomes for PRAME deletions in the context of Ig-λ expression, as shown in Figure 1 (2). In particular, we demonstrate that PRAME deletions are independently associated with outcomes in multivariable analysis, making it unlikely that PRAME deletions are a pure surrogate for the prognostic effects of Ig-λ usage. As described by Mraz and Pospisilova, the association of PRAME deletion and Ig-λ rearrangement and expression is not absolute, and PRAME deletion is likely dependent on the exact V segment usage (3). Consistently, we did not observe PRAME deletions in the majority of patients expressing Ig-λ, and, interestingly, a minority of patients with PRAME deletions expressed Ig-κ. Indeed, it remains an open question whether heterozygous or homozygous PRAME deletions can occur during the process of B cell lymphomagenesis, and potentially at the time point of the germinal center (GC) reaction in GC-derived diffuse large B cell lymphomas (DLBCLs). Regardless of the deletion-generating mechanism, our study brings into focus PRAME loss–associated cell-autonomous and tumor microenvironment phenotypes that are under selective pressure in DLBCL. Our discovery that both genomic PRAME deletion and EZH2 mutations converge on reduced PRAME expression and downstream phenotypes underscores the pathogenic relevance of the PRAME gene in B cell lymphoma.
Version 1. 07/15/2022
Electronic publication
Version 2. 07/18/2022
Text error corrected: lambda symbol changed to kappa
Footnotes
Conflict of interest: CS has performed consultancy for Seattle Genetics, Curis Inc., Roche, AbbVie, Juno Therapeutics, and Bayer and has received research support from Epizyme, Bristol-Myers Squibb, and Trillium Therapeutics Inc.
Address correspondence to: Christian Steidl, British Columbia Cancer, 675 West 10th Ave., Room 12-110, Vancouver, British Columbia, V5Z 1L3, Canada. Email: CSteidl@bccancer.bc.ca.
Reference information: J Clin Invest. 2022;132(14):e161979. https://doi.org/10.1172/JCI161979.
See the related article at Tumor-associated antigen PRAME exhibits dualistic functions that are targetable in diffuse large B cell lymphoma .
See the related Letter to the Editor at Genetic mechanism for the loss of PRAME in B cell lymphomas.
Contributor Information
Katsuyoshi Takata, Email: ktakata@bccrc.ca.
Christian Steidl, Email: CSteidl@bccancer.bc.ca.
References
- 1.Mraz M, et al. The origin of deletion 22q11 in chronic lymphocytic leukemia is related to the rearrangement of immunoglobulin lambda light chain locus. Leuk Res. 2013;37(7):802–808. doi: 10.1016/j.leukres.2013.03.018. [DOI] [PubMed] [Google Scholar]
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