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Ferrata Storti Foundation
Haematologica 2021 Volume 106(10):2682-2693
MAPK and JAK-STAT pathways dysregulation in plasmablastic lymphoma
Joan Enric Ramis-Zaldivar,1,2* Blanca Gonzalez-Farre,1,2* Alina Nicolae,3 Svetlana Pack,3 Guillem Clot,1,2 Ferran Nadeu,1,2 Anja Mottok,4 Heike Horn,5,6,7 Joo Y. Song,8 Kai Fu,9 George Wright,10 Randy D. Gascoyne,4 Wing C. Chan,8 David W. Scott,4,11 Andrew L. Feldman,12 Alexandra Valera,1 Anna Enjuanes,1,2 Rita M. Braziel,13 Erlend B. Smeland,14,15 Louis M. Staudt,16 Andreas Rosenwald,17 Lisa M. Rimsza,18 German Ott,5,6,7 Elaine S. Jaffe,3 Itziar Salaverria1,2,# and Elias Campo1,2,19,# for the Leukemia and Lymphoma Molecular Profiling Project (LLMPP)
1Hematopathology Unit, Hospital Clínic of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; 2Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; 3Hematopathology Section, Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA; 4Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; 5Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Stuttgart, Germany; 6Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; 7University of Tübingen, Tübingen, Germany; 8Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA; 9Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA; 10Biometric Research Branch, Division of Cancer Diagnosis and Treatment, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; 11Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; 12Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; 13Department of Clinical Pathology, Oregon Health & Science University, Oregon, OR, USA; 14Department of Immunology and Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway; 15Oslo University Hospital, Oslo, Norway; 16Lymphoid Malignancies Branch, Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA; 17Institute of Pathology, University of Wur̈ zburg, Wur̈ zburg, Germany; 18Department of Laboratory Medicine and Pathology, Mayo Clinic, Phoenix, AZ, USA and 19University of Barcelona, Barcelona, Spain
*JER-Z and BG-F contributed equally as co-first atuhors. #IS and EC contributed equally as co-senior atuhors.
ABSTRACT
Plasmablastic lymphoma (PBL) is an aggressive B-cell lymphoma with an immunoblastic/large-cell morphology and terminal B-cell differentiation. The differential diagnosis from Burkitt lymphoma, plasma cell myeloma and some variants of diffuse large B-cell lymphoma may be challenging because of the overlapping morphological, genetic and immunophenotypic features. Furthermore, the genomic landscape in PBL is not well known. To characterize the genetic and molecular hetero- geneity of these tumors, we investigated 34 cases of PBL using an inte- grated 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 sug- gested a cooperative action between MYC alterations and MAPK (49%) and JAK-STAT (40%) signaling pathways. Of note, Epstein-Barr virus (EBV)-negative 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 in relation to EBV infection.
Non-Hodgkin Lymphoma
Correspondence:
ELIAS CAMPO
ecampo@clinic.cat
Received: September 24, 2020. Accepted: March 31, 2021. Pre-published: May 6, 2021.
https://doi.org/10.3324/haematol.2020.271957 ©2021 Ferrata Storti Foundation
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