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Oncogenic somatic mutations in plasmablastic lymphoma.
mutations have not been previously described in DLBCL NOS.26 SGK1 has been suggested to be a negative regula- tor of NOTCH signaling, enhancing NOTCH protein degradation and reducing its activation by γ-secretase.29 Other mutations found were SMARCA4pR1005Q and TP53pR273H.
Of note MAPK/ERK pathway-activating mutations involving BRAF (BRAFpV600E, BRAFpG469A) were found in two cases, both EBV-negative. BRAF mutations have been observed, rarely, in related neoplasms such as multi- ple myeloma. Previous studies found BRAF mutations in 4% of cases of multiple myeloma;30 they were associated with aggressive clinical features, a plasmablastic pheno- type and clonal evolution,31,32 with obvious clinical impli- cations for targeted therapy.
In addition to the genetic profile of the cases, we also explored the composition of the tumor microenviron- ment and the expression of immune-checkpoint markers in both the neoplastic and other lymphoid and histiocyt- ic/dendritic populations. Our results confirm those of previous studies showing an enrichment in TAM that express CD163 and PD-L1. The PBL also had a significant population of CD8-positive T cells, irrespective of the almost absent expression of MHCII/HLA by the neoplas- tic cells.9 Importantly, together with CD8-positive T cells, there was a distinct population of PD1-positive T cells. In the PBL cases that we studied, EBV did not influ- ence the immune populations, with regards to the con- tent of TAM and CD8-positive and PD1-positive T cells quantified in the tissue. Furthermore, in our series, PD-L1 expression by the neoplastic cells was found in 20% of the cases analyzed, similarly to previously published series,8 and there was no association between EBV infec- tion by tumor cells and PD-L1 expression, since PD-L1 was found in both EBV-positive and EBV-negative vari- ants and most of the EBV-positive cases were PD-L1-neg- ative. These findings are in agreement with previously published data on PBL, with variable expression of PD- L1 ranging from 20 to 44%, by the neoplastic population.8,33 In our series, however, we did not confirm an association between EBV infection and PD-L1 expres- sion, suggested by others.8 This difference may be due to a combination of factors, including different clones used for the detection of PD-L1 expression (22C3 clone in this study, SP142 in others8) and different quantification and statistical methods used. In addition another biological factor related to the uncommon PD-L1 expression in PBL cases could be related to the usual latency pattern found in these cases, since PD-L1 expression in EBV-positive post-transplant lymphoproliferative disorder has been strongly associated with EBV latency patterns 2 and 334
while PBL cases usually have EBV latency pattern 1.7 Notably one of our cases points to STAT3 activation as a potential cause for PD-L1 overexpression in PBL. Collectively our results on the microenvironment and immune-checkpoint expression in PBL indicate a poten- tial for immune checkpoint interference in patients with this type of lymphoma.
In summary, in this study we found that the mutational profile of PBL was related to EBV infection in the tumor cells and identified recurrent genetic events in MYC, STAT3 and PRDM1/Blimp1 that were associated with EBV- positive disease. MYC genetic alterations (including translocations and amplification) and SH2 domain STAT3 mutations led to MYC and phospho-STAT3 (Tyr705) pro- tein overexpression, respectively. Other somatic mutations including BRAFpV600E, MYD88pL265P, NOTCH2pR2400* and TP53pR273H, appeared in EBV-negative disease, sug- gesting an overlapping mutational profile with both multi- ple myeloma and DLBCL NOS. Furthermore, the tumor microenvironment in PBL was characterized by an enrich- ment in PD-L1-positive TAM and PD1 reactive T lympho- cytes with expression of PD-L1 by the neoplastic tumor cells in a fraction of cases. Novel molecular targets derived from the present study include MYC and STAT3 activa- tion, MAPK/ERK and NOTCH2 pathway mutations and immune-checkpoint interference.
Disclosures
No conflicts of interest to disclose.
Contributions
JGR and NMM performed research, analyzed data and approved the paper. SGV, RT, SB and MG analyzed data and approved the paper. SL and EDA performed research, provided clinical data and approved the paper. AGM and AGP performed research and approved the paper. CV and JK provided clinical data and approved the paper. SMM designed and performed research, analyzed data, and wrote and approved the paper.
Funding
This study was supported by grants from MINECO (PI16/1397, SMM, Principal Investigator) and IDIVAL (NEXTVAL 15/09, SMM, Principal Investigator). NMM was supported by Asociación Española contra el Cancer (AECC).
Acknowledgments
The authors acknowledge the Valdecilla Tumor Biobank Unit (Tissue Node, PT13/0010/0024) for their skillful handling and processing of tissue samples and all their clinical colleagues and pathologists who provided clinical data and samples for this research study.
References
1. Swerdlow S, Campo E, Harris NL, et al. (Editors). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Fourth edition. IARC 2008.
2. Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classi- fication of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood. 2011;117(19):5019- 5032.
3.
4.
Delecluse HJ, Anagnostopoulos I, Dallenbach F, et al. Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection. Blood. 1997;89(4):1413-1420. Montes-Moreno S, Gonzalez-Medina AR, Rodriguez-Pinilla SM, et al. Aggressive large B-cell lymphoma with plasma cell dif- ferentiation: immunohistochemical charac- terization of plasmablastic lymphoma and diffuse large B-cell lymphoma with partial plasmablastic phenotype. Haematologica. 2010;95(8):1342-1349.
5. Colomo L, Loong F, Rives S, et al. Diffuse large B-cell lymphomas with plasmablastic differentiation represent a heterogeneous group of disease entities. Am J Surg Pathol. 2004;28(6):736-747.
6. Chapman J, Gentles AJ, Sujoy V, et al. Gene expression analysis of plasmablastic lym- phoma identifies downregulation of B-cell receptor signaling and additional unique transcriptional programs. Leukemia. 2015;29(11):2270-2273.
7. Gravelle P, Péricart S, Tosolini M, et al. EBV infection determines the immune hall-
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