MicroRNAs sequencing unveils distinct molecular subgroups of plasmablastic lymphoma.

Maria Raffaella Ambrosio,Giuseppe Lo Bello,Amhed Yonis,Lorenzo Leoncini,Stefano Lazzi,Matteo Picciolini,Alessandro Ginori,Sara Gazaneo,Mohsen Navari,Lucia Mundo,Prasad Satya Vara,Pier Paolo Piccaluga,Shaheen Sayed,Stefano Ascani,Leonardo Del Porro

doi:10.18632/oncotarget.22219

Abstract

Plasmablastic lymphoma (PBL) is an aggressive lymphoma, often arising in the context of immunodeficiency and associated with Epstein-Barr virus (EBV) infection. The most frequently detected genetic alteration is the deregulation of MYC gene through the translocation - t(8;14)(q24;q32). The diagnosis of PBL is often challenging because it has an overlap in morphology, immunophenotype, cytogenetics and virus association with other lymphomas and plasma cell neoplasms; further, its molecular basis remains elusive. In the present study we aimed to better define the possible contribution of EBV infection as well as miRNA deregulation in PBL pathogenesis.We studied 23 cases of PBL, 19 Burkitt lymphomas (BL), and 17 extra-medullary plasmacytoma (EMPC). We used qPCR and immunohistochemistry to assess EBV latency patterns, while micro-RNA (miRNA) profiling was performed by next generation sequencing (Illumina) and validated by qPCR.Our analysis revealed a non-canonical EBV latency program with the partial expression of some proteins characterizing latency II and the activation of an abortive lytic cycle. Moreover, we identified miRNA signatures discriminating PBL from BL and EMPC. Interestingly, based on the miRNA profile, PBL appeared constituted by two discrete subgroups more similar to either BL or EMPC, respectively. This pattern was confirmed in an independent set of cases studied by qPCR and corresponded to different clinico-pathological features in the two groups, including HIV infection, MYC rearrangement and disease localization.In conclusion, we uncovered for the first time 1) an atypical EBV latency program in PBL; 2) a miRNA signature distinguishing PBL from the closest malignant counterparts; 3) the molecular basis of PBL heterogeneity.

Highlights

Plasmablastic lymphoma (PBL) is a rare highly aggressive lymphoma that occurs most often in the context of Human Immunodeficiency Virus (HIV)infection (40-50%), or in other settings of decreased immune surveillance [1]
The diagnosis of PBL is challenging because it has an overlap in cytomorphologic and immunophenotypic features with plasma cell neoplasms and with lymphomas that show blastic appearance [3]
We checked the expression of EBNA-1, EBNA-2, EBNA-3, LMP-1, LMP-2A, EBER transcripts, BZLF-1/ ZEBRA, BMRF-1/Ea-D, BHRF-1/Ea-R, BLLF1/gp350 across the 13 PBL cases (12 Epstein-Barr virus (EBV)-positive and 1 EBVnegative)

Summary

Introduction

Plasmablastic lymphoma (PBL) is a rare highly aggressive lymphoma that occurs most often in the context of Human Immunodeficiency Virus (HIV)infection (40-50%), or in other settings of decreased immune surveillance [1]. Tumor cells have a welldefined morphology resembling B-immunoblasts, and express plasma cells markers [1]. The diagnosis of PBL is challenging because it has an overlap in cytomorphologic and immunophenotypic features with plasma cell neoplasms and with lymphomas that show blastic appearance (i.e. more immature, plasmablastlike morphology) [3]. Even using a comprehensive panel of immunostains, a confident differential diagnosis between PBL and anaplastic or plasmablastic extramedullary plasmacytoma (EMPC) is not always possible. The differential diagnosis between PBL and other lymphoma types with blastic appearance is often straightforward due to the lack of B-cell marker expression in PBL. Other overlaps include cell morphology with the starry sky appearance, the high proliferation rate, the MYC protein over-expression and the association with EBV infection

Objectives

Methods

Results

Conclusion