Page 163 - 2021_10-Haematologica-web

Genetic landscape of plasmablastic lymphoma
The JAK-STAT pathway was also mutated in 40% of our cases. We found recurrent activating STAT3 variants located in the SH2 domain, in addition to inactivating mutations in SOCS1, a negative regulator of the JAK-STAT pathway. Activating STAT3 mutations and expression of the acti- vated protein are frequently seen in T-cell and NK-cell malignancies but are rare in B-cell lymphomas, being pre- viously described only in high-grade B-cell lymphoma, a subset of CD30+ DLBCL and ALK+ large B-cell lymphoma, which also has a plasmablastic phenotype.29,39,40 Moreover, these STAT3 mutations have been suggested to confer hydrophobicity, facilitating the activation of STAT3 through Y705 phosphorylation and the consequent upregulation of STAT3 downstream target genes.29
Immunohistochemical staining for p-STAT3 demon- strated positivity in 67% of the cases independently of the STAT3 mutational status. The same results were obtained by Liu et al. In addition, no differences in the expression of JAK-STAT pathways were observed in STAT3-mutated and wild-type tumors. Although the number of cases is limited, these results suggest that PBL may have alternative mechanisms of STAT pathway acti- vation.10 Interestingly, plasmablastic PCM were negative for p-STAT3. The potential diagnostic value of this differ- ence deserves further confirmation.
Independently of these activating mutations, the JAK- STAT pathway is also deregulated in PCM and ABC- DLBCL, promoting cell survival and proliferation.41,42 In addition, the interaction of IL6 with its receptor IL6R has been described to induce STAT3 activation in PCM cell lines.43 Interestingly, a newly established PBL cell line has been demonstrated to be dependent on IL6 for prolifera- tion and survival.44 All these findings suggest the impor- tance of IL6/JAK/STAT3 signaling in the pathogenesis of PBL disease.
On the other hand, in addition to MYC rearrange- ments, genes governing the cell cycle were also affected in PBL by other mechanisms including bi-allelic inactiva- tion of important regulator genes such as TP53 and CDKN2A. Of note, these TP53 alterations, including mutations and deletions, were restricted to EBV-negative PBL, without other associated clinical, morphological or molecular features. The low frequencies of TP53 muta- tions identified in previous studies is probably due to the small number of EBV-negative cases in those series (Online Supplementary Figure S12).8,10
Interestingly, the mutational landscape of PBL differed from that of BL since it lacked variants affecting genes related to BL pathogenesis such as ID3, SMARCA4 and TCF3. Moreover, compared with ABC-DLBCL, PBL lacked typical MYD88-L265P and CD79B mutations, affecting NFκB pathway. Finally, PBL resembles PCM for the presence of mutations affecting the MAPK pathway.26 Mutations in this pathway were detected as clonal or subclonal in different cases. In contrast, TP53 alterations and NRAS mutations were frequently clonal, suggesting that they are early events in PBL in addition to MYC rearrangements.
As previously observed in other lymphoma subtypes, our results suggest that EBV-positivity defines a specific PBL phenotype with particular molecular properties such as lower levels of genetic complexity, and distinct pathogenic mechanisms.9,45-48 Specifically, EBV-positive PBL showed more frequent STAT3 mutations whereas inactivating TP53 alterations (mutations, deletions and CNN-LOH) were sig-
nificantly enriched in EBV-negative tumors, which have lower expression of p53 signaling pathway-related genes. In BL, EBV positivity has also been associated with fewer driv- er mutations, especially among apoptosis-related genes such as TP53.45 Additionally, similar to PBL, EBV-positive DLBCL had relatively fewer genomic alterations than EBV- negative DLBCL, whereas EBV-negative cases had more 17p deletions.48 This suggests two different mechanisms to avoid apoptosis in which TP53 depletion substitutes for the anti-apoptotic effect that EBV infection exerts in the cell. In addition, EBV-negative PBL have a higher frequency of mutations affecting epigenome/chromatin modifiers and NFκB signaling pathways. In ABC-DLBCL, genetic alter- ations of BCR-TLR pathways lead to high NFκB activity whichinducesproductionofIL-6andIL-10.49,50Theseobser- vations suggest that an autocrine action of IL-6 could also occur in EBV-negative PBL, activating the JAK-STAT path- way as an alternative mechanism to STAT3 mutations pres- entinEBV-positivecases.
In summary, we used an integrative approach of FISH, copy number and next-generation sequencing mutational analyses in a large series of PBL. Our results revealed a spe- cific PBL genetic landscape which, differing from that of other related lymphoma entities, is characterized by recur- rent alterations in the MAPK and JAK-STAT pathways in addition to previously known MYC rearrangements. Moreover, we identified a distinct mutation profile for EBV- positive and EBV-negative cases, a finding observed in other forms of aggressive B-cell lymphoma. The detection of recurrently altered MAPK and JAK-STAT pathways in PBL opens new perspectives in the biology of this disease, iden- tifying possible new targets for therapy.
Disclosures
No conflicts of interest to disclose.
Contributions
JER-Z performed research, analyzed data and wrote the manu- script; BG-F. performed morphological diagnoses, analyzed data and wrote the manuscript; GC, FN, AM, HH, GW, DWS, AV and AE performed research and analyzed data; AN, SP, JYS, KF, RDG, WCC, ALF, RMB, EBS, LMS, AR, LMR, GO and ESJ reviewed and interpreted pathological and/or clinical data; IS per- formed research, analyzed data, designed research and wrote the manuscript; EC performed morphological analyses, designed research and wrote the manuscript. All authors approved the final version of the manuscript.
Acknowledgments
We thank Noelia Garcia, Miriam Prieto, Silvia Martín, and Helena Suarez for their excellent technical assistance. We are indebted to the IDIBAPS Genomics Core Facility and to the HCB- IDIBAPS Biobank-Tumor Bank.
Funding
This work was supported by Spanish Ministerio de Economía y Competitividad, grant RTI2018-094274-B-I00 (to EC), National Institutes of Health “Molecular Diagnosis, Prognosis, and Therapeutic Targets in Mantle Cell Lymphoma” (grant 1P01CA229100), and the European Regional Development Fund “Una manera de fer Europa”. Generalitat de Catalunya Suport Grups de Recerca (2017-SGR-1107 to IS and 2017- SGR-1142 to EC), JER-Z was supported by a fellowship from Generalitat de Catalunya AGAUR FI-DGR 2017 (2017 FI_B01004). EC is an Academia Researcher of the "Institució
haematologica | 2021; 106(10)
2691