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Haematologica 2021 Volume 106(4):1120-1128
Non-Hodgkin Lymphoma
Genetic lesions in MYC and STAT3 drive oncogenic transcription factor overexpression in plasmablastic lymphoma
Julia Garcia-Reyero,1,2 Nerea Martinez Magunacelaya,2 Sonia Gonzalez de Villambrosia,3 Sanam Loghavi,4 Angela Gomez Mediavilla,2 Raul Tonda,5 Sergi Beltran,5 Marta Gut,5 Ainara Pereña Gonzalez,2 Emmanuel D’Ámore,6 Carlo Visco,7 Joseph D. Khoury4 and Santiago Montes-Moreno1,2
1Anatomic Pathology Service, Hospital Universitario Marqués de Valdecilla/IDIVAL, Universidad de Cantabria, Santander, Spain; 2Translational Hematopathology Laboratory, IDIVAL, Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Santander, Spain; 3Cytogenetics Unit, Department of Hematology, HUMV, Santander, Spain; 4Hematopathology Department, MD Anderson Cancer Center, Houston, TX, USA; 5Centre Nacional d’Anàlisi Genòmica. Barcelona Institute of Science and Technology (BIST). Universitat Pompeu Fabra, Barcelona, Spain; 6Departments of Pathology and Hematology, San Bortolo Hospital, Vicenza, Italy and 7Department of Medicine, Section of Hematology, University of Verona, Verona, Italy
ABSTRACT
The mutational profile of plasmablastic lymphoma has not been described. We performed a targeted, exonic next-generation sequencing analysis of 30 plasmablastic lymphoma cases with a B- cell lymphoma-dedicated panel and fluorescence in situ hybridization for the detection of MYC rearrangements. Complete phenotyping of the neoplastic and microenvironmental cell populations was also performed. We identified an enrichment in recurrent genetic events in MYC (69% with MYC translocation or amplification and three cases with missense point mutations), PRDM1/Blimp1 and STAT3 mutations. These gene mutations were more frequent in Epstein-Barr virus (EBV)-positive dis- ease. Other genetic events included mutations in BRAF, EP300, BCR (CD79A and CD79B), NOTCH pathway (NOTCH2, NOTCH1 and SGK1) and MYD88pL265P. Immunohistochemical analysis showed con- sistent MYC expression, which was higher in cases with MYC rearrange- ments, together with phospho-STAT3 (Tyr705) overexpression in cases with STAT3 SH2 domain mutations. Microenvironmental cell popula- tions were heterogeneous and unrelated to EBV, with enrichment of tumor-associated macrophages (TAM) and PD1-positive T cells. PD-L1 was expressed in all cases in the TAM population but only in the neo- plastic cells in five cases (4 of 14 EBV-positive cases). HLA expression was absent in the majority of cases of plasmablastic lymphoma. In sum- mary, the mutational profile of plasmablastic lymphoma is heteroge- neous and related to EBV infection. Genetic events in MYC, STAT3 and PRDM1/Blimp1 are more frequent in EBV-positive disease. An enrich- ment in TAM and PD1 reactive T lymphocytes is found in the microen- vironment of plasmablastic lymphoma and a fraction of the neoplastic cells express PD-L1.
Introduction
Plasmablastic lymphoma (PBL) is an aggressive type of non-Hodgkin B-cell lym- phoma defined as a high-grade large B-cell neoplasm with plasma cell phenotype (i.e., loss of B-cell antigens with downregulation of CD20 and PAX5 expression and overexpression of PRDM1/Blimp1 and XBP1s).1-4
Epstein-Barr virus (EBV) infection is found in the majority of cases but is not required for the development of a plasmablastic phenotype since clear-cut PBL can be negative for EBV.3-5 In addition, recent evidence suggests that EBV or human immunodeficiency virus (HIV) status does not influence the gene expression profile
Correspondence:
SANTIAGO MONTES MORENO
santiago.montes@scsalud.es
Received: March 1, 2020. Accepted: April 9, 2020. Pre-published: April 9, 2020.
https://doi.org/10.3324/haematol.2020.251579
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