Genomic Characterization of HIV-Associated Plasmablastic Lymphoma Identifies Pervasive Mutations in the JAK–STAT Pathway

Abstract

Plasmablastic lymphoma (PBL) is an aggressive B-cell non-Hodgkin lymphoma associated with immunodeficiency in the context of human immunodeficiency virus (HIV) infection or iatrogenic immunosuppression. While a rare disease in general, the incidence is dramatically increased in regions of the world with high HIV prevalence. The molecular pathogenesis of this disease is poorly characterized. Here, we defined the genomic features of PBL in a cohort of 110 patients from South Africa (15 by whole-exome sequencing and 95 by deep targeted sequencing). We identified recurrent mutations in genes of the JAK-STAT signaling pathway, including STAT3 (42%), JAK1 (14%), and SOCS1 (10%), leading to its constitutive activation. Moreover, 24% of cases harbored gain-of-function mutations in RAS family members (NRAS and KRAS). Comparative analysis with other B-cell malignancies uncovered PBL-specific somatic mutations and transcriptional programs. We also found recurrent copy number gains encompassing the CD44 gene (37%), which encodes for a cell surface receptor involved in lymphocyte activation and homing, and was found expressed at high levels in all tested cases, independent of genetic alterations. These findings have implications for the understanding of the pathogenesis of this disease and the development of personalized medicine approaches. SIGNIfICANCe: Plasmablastic lymphoma is a poorly studied and extremely aggressive tumor. Here we define the genomic landscape of this lymphoma in HIV-positive individuals from South Africa and identify pervasive mutations in JAK-STAT3 and RAS-MAPK signaling pathways. These data offer a genomic framework for the design of improved treatment strategies targeting these circuits.

The Genomic Landscape of HIV-Associated Plasmablastic Lymphoma

“…Genetic lesions in PBL. The graph summarizes main genetic lesions and other factors in the pathogenesis of PBL reported by Liu and colleagues (6), and also findings from earlier work (EBV infection, MYC translocations). Mutations in STAT3, JAK1/2, NOTCH1, and RAS stand exemplarily for mutations in various members of each of these pathways or gene families.…”

“…In this issue of Blood Cancer Discovery, a first large-scale analysis of the landscape of somatic mutations in human immunodeficiency virus (HIV)-associated PBL is presented by Liu and colleagues (6). Fifteen cases of such lymphomas were studied by whole-exome sequencing and a further 95 lymphomas by targeted deep sequencing for 34 candidate genes, partly selected on the basis of the results of the initial exome sequencing.…”

“…Forty-six PBL cases were studied for copy-number alterations (6). One of the main findings was the detection of focal copy-number gains involving the CD44 gene.…”

Phenogenomic heterogeneity of post-transplant plasmablastic lymphomas

“…Nor was there a significant difference in the number of variants between patients that died of PBL versus those that did not (4.7 mean pathogenic/likely pathogenic and 10.0 total SNVs vs. expression of B-cell receptor and NF-κB signaling pathway genes. 7,9 However, microRNA expression analysis has suggested two different subclasses of PBL, either resembling Burkitt lymphoma or EOP. 10 Chang et al documented overlapping chromosome aberrations between PBLs and IC-DLBCLs as well as PBL specific segmental gains at chromosomes 1p and 1q by array comparative genomic hybridization.…”

“…2 Prior studies of mostly HIV-associated PBL highlighted the prognostic significance of disease stage and EBV status [2][3][4] and genomic analyses have revealed frequent MYC rearrangements, heterogeneous chromosome/DNA copy number abnormalities, [5][6][7] variable transcriptional and microRNA profiles, 2,[8][9][10] and recently, recurrent mutations in JAK/STAT, MAPK and NOTCH pathway genes. 7,11 PBLs occurring after solid organ transplantation (PT-PBLs) are an uncommon type of posttransplant lymphoproliferative disorder (PTLD), accounting for 6-7% of PTLDs and constituting a minor fraction (5-14%) of all PBLs. 2-4, 12, 13 Only limited data regarding the pathological and molecular features of PT-PBL have been reported.…”