MAP-kinase and JAK-STAT pathways dysregulation in plasmablastic lymphoma.

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Plasmablastic lymphoma (PBL) is an aggressive B-cell lymphoma with an immunoblastic/large cell morphology and plasmacytic differentiation. The differential diagnosis with Burkitt lymphoma (BL), plasma cell myeloma (PCM) and some variants of diffuse large B-cell lymphoma (DLBCL) may be challenging due to the overlapping morphological, genetic and immunophenotypic features. Furthermore, the genomic landscape in PBL is not well known. To characterize the genetic and molecular heterogeneity of these tumors, we investigated thirty-four PBL using an integrated approach, including fluorescence in situ hybridization, targeted sequencing of 94 B-cell lymphoma related genes, and copy-number arrays. PBL were characterized by high genetic complexity including 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 (37%), NRAS and TP53 (33%), MYC and EP300 (19%) and CARD11, SOCS1 and TET2 (11%). Pathway enrichment analysis suggested a cooperative action between MYC alterations and MAPK (49%) and JAK-STAT (40%) signaling pathways. Of note, EBVnegative PBL cases had higher mutational and copy-number load and more frequent TP53, CARD11 and MYC mutations, whereas EBV-positive PBL tended to have more mutations affecting the JAK-STAT pathway. In conclusion, these findings further unravel the distinctive molecular heterogeneity of PBL identifying novel molecular targets and the different genetic profile of these tumors related to EBV infection.

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Authors: Joan Enric Ramis-Zaldivar, Blanca Gonzalez-Farre, Alina Nicolae, Svetlana Pack, Guillem Clot, Ferran Nadeu, Anja Mottok, Heike Horn, Joo Y Song, Kai Fu, George Wright, Randy D Gascoyne, Wing C Chan, David W Scott, Andrew L Feldman, Alexandra Valera, Anna Enjuanes, Rita M Braziel, Erlend B Smeland, Louis M Staudt, Andreas Rosenwald, Lisa M Rimsza, German Ott, Elaine S Jaffe, Itziar Salaverria, Elias Campo