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Editorials
evident that the same morphological and phenotypic features can be sustained by a quite variable landscape of genetic aberrations with clones competing with each other within the same neoplasm and under the influ- ence of the microenvironment, thus leading to possible clonal selection, chemoresistance and relapse.6
Ramis-Zaldivar et al. show that PBL is characterized by high genetic complexity with very frequent MYC translocations (87%), gains of 1q21.1-q44, trisomy 7, 8q23.2-q24.21, 11p13-p11.2, 11q14.2-q25, 12p and 19p13.3-p13.13, losses of 1p33, 1p31.1-p22.3, 13q and 17p13.3-p11.2, and recurrent mutations of STAT3, NRAS, TP53, MYC, EP300, CARD11, SOCS1, and TET2 (here listed in order of decreasing frequency).1 Pathway enrichment analysis suggested a cooperative action between MYC alterations and MAPK and JAK-STAT signaling pathways. These alterations have been at least in part reported in previous studies.7,8 However, Ramis- Zaldivar et al. achieved three major goals. First, they analyzed the clonal evolution in PBL and found that in 24 tumors the cancer cell fraction included 250 copy number alterations and 107 mutations. Most of these alterations revealed a wide spectrum of cancer cell frac- tions with the exception of TP53 mutations, 17 losses and 13q deletions, which turned out to be clonal. Notably, clonal and subclonal mutations affected the same protein domains, suggesting that the subclonal ones give similar advantage to the neoplastic cell. This is in keeping with what has been observed in liquid biopsy studies, which have revealed that the mutational landscape of diffuse large B-cell lymphoma is definitely wider in circulating tumoral DNA than in the diagnostic biopsy.9 This finding underlines the potential occurrence of different clones at different anatomic sites (clonal het- erogeneity) in lymphoid malignancies characterized by high genetic complexity, clones which can be selected by therapy and cause disease resistance or relapse.10 Second, the recorded constellation of genetic alterations could represent the rationale for targeted therapies (Figure 1), which are indeed urgently needed in the light of the poor response to conventional chemotherapy, including intensified regimens. The third important achievement of the study by Ramis-Zaldivar et al. con- sists in the demonstration of a clear-cut genetic differ- ence between EBV-positive and EBV-negative cases of PBL. In particular, the latter showed greater genetic complexity and higher mutational loads than the EBV- positive ones. EBV-negative cases were characterized by more frequent mutations affecting TP53, CARD11 and MYC as well as epigenome/chromatin modifiers, cell cycle and the NF-κB pathway. Conversely, EBV-positive cases tended to carry frequent mutations involving genes of the JAK-STAT pathway. These findings are of interest for practical and conceptual reasons. They sug- gest different therapeutic targets depending on EBV- positivity or negativity. Furthermore, they strengthen the understanding of the different pathobiology of virus-infected lymphomas. By RNA sequencing, Abate et al. showed that eight (40%) of 20 cases of endemic Burkitt lymphoma from Uganda carried infection by Herpesviridae members other than EBV, thus suggesting a polyviral condition, and revealed a mutational land-
scape different from that of sporadic Burkitt lymphoma (with lower frequencies of MYC, ID3, TCF3 and TP53 mutations, higher frequency of ARID1A mutations, and the occurrence of not previously detected RHOA and CCNF mutations).11 These findings suggested, as in the report from Ramis-Zaldivar et al.,1 a dual mechanism of transformation in epidemic and sporadic Burkitt lym- phoma: virus versus mutation-driven, respectively.
The ever increasing application of high-resolution approaches to the analysis of malignant lymphomas is unraveling a scenario much more intriguing than thought only a few years ago. Within the body of a dis- tinct entity as defined by the WHO classification,2 there are tumors with different pathobiological characteris- tics, which offer different targets for ad hoc therapies. This has practical implications for the management of patients as well as for the design of innovative therapeu- tic trials, if the final goal is to move to precision medi- cine.
Disclosures
No conflicts of interest to disclose.
Contributions
SAP wrote the manuscript; ED commented and revised it; SM created the figure.
Funding
Supported by the grant AIRC 5x1000 n. 21198.
References
1. Ramis-Zaldivar JE, Gonzales-Farre B, Nicolae A, et al. MAPK and JAK-STAT pathways dysregulation in plasmablastic lymphoma. Haematologica. 2021;106(10):2682-2693.
2. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumour of Haematopoietic and Lymphoid Tissues, Revised 4th edition. 2017. IARC Press, Lyon.
3. Castillo JJ, Bibas M, Miranda RN. The biology and treatment of plasmablastic lymphoma. Blood. 2015;125(15):2323-2330.
4. Castillo JJ, Furman M, Beltrán BE, et al. Human immunodeficiency virus-associated plasmablastic lymphoma: poor prognosis in the era of highly active antiretroviral therapy. Cancer. 2012;118(21): 5270-5277.
5. Raychaudhuri R, Qualtieri J, Garfall AL. Axicabtagene ciloleucel for CD19+ plasmablastic lymphoma. Am J Hematol. 2020;95(1): E28-E30.
6.Kotlov N, Bagaev A, Revuelta MV, et al. Clinical and biological subtypes of B-cell lymphoma revealed by microenvironmental sig- natures. Cancer Discov. 2021;11(6):1468-1489.
7.Garcia Reyero J, Martinez Magunacelaya N, Gonzalez de Villambrosia S, et al. Genetic lesions in MYC and STAT3 drive oncogenic transcription factor overexpression in plasmablastic lymphoma. Haematologica. 2021;106(4): 1120-1128.
8. Liu Z, Filip I, Gomez K, et al. Genomic characterization of HIV- associated plasmablastic lymphoma identifies pervasive mutations in the JAK-STAT pathway. Blood Cancer Discov. 2020;1(1):112- 125.
9. Kurtz DM, Scherer F, Jin MC, et al. Circulating tumor DNA meas- urements as early outcome predictors in diffuse large B-cell lym- phoma. J Clin Oncol. 2018;36(28):2845-2853.
10. Derenzini E, Iacobucci I, Agostinelli C, et al. Therapeutic implica- tions of intratumor heterogeneity for TP53 mutational status in Burkitt lymphoma. Exp Hematol Oncol. 2015;4:24.
11. Abate F, Ambrosio MR, Mundo L, et al. Distinct viral and muta- tional spectrum of endemic Burkitt lymphoma. Plos Pathogens. 2015;11(10):e1005158.
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