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.

Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma

“…Our analyses in PBL subcohorts further showed that STAT3 mutations predominantly occur in HIV-associated PBLs as these lymphomas harbored significantly more frequently STAT3 mutations compared to other PBL subtypes. In line with our data, a recently published analysis of HIV-associated PBLs reported STAT3 mutations at the same identified mutational hotspots in 42% of investigated cases 9 .…”

“…Roughly 50% of PBL cases harbor MYC translocations that usually rearrange MYC to the heavy chain immunoglobulin locus suggesting an essential role of MYC in the biology of PBL. Recently, a small study using targeted sequencing identified PRDM1 , STAT3 , BRAF , and EP300 mutations in primary PBL samples 8 , whereas another analysis focused on HIV-associated PBL that revealed recurrent mutations of the JAK-STAT pathway 9 . However, due to the small sample size respectively the focus on HIV positive PBL, the landscape of genetic aberrations in PBL, and the exact functional role of these abnormalities in the molecular pathogenesis of PBL remain largely unknown.…”

EBV‐positive HIV‐associated diffuse large B cell lymphomas are characterized by JAK/STAT (STAT3) pathway mutations and unique clinicopathologic features

“…In addition, we saw mutations associated with SOCS1 (two cases in EBV-positive HIV DLBCL), which is a negative regulator for STAT3 23 and which is also found to be mutated in cases of HIV-associated plasmablastic lymphoma. 14 These findings raise the possibility that EBV-positive plasmablastic lymphoma and EBVpositive HIV-DLBCL may share some common genetic alterations in addition to EBV association, a tendency toward post-germinal centre/terminally differentiated B-cell origin, development in patients with more profound immunodeficiency with lower CD4 counts, and worse OS.…”

“…All but one of the cases with a STAT3 abnormality was within the SH2 domain. Since the RAS-MAPK pathway has been implicated in other HIV-associated lymphomas, 14,15 we investigated genes related to this pathway and found three EBV-positive HIVassociated DLBCL with NRAS mutations and none in the EBV-negative HIV-DLBCL. One case had a mutation with BRAF but the EBV status of this HIV-DLBCL is unknown.…”

“…Mutations affecting the JAK/STAT pathway, particularly the oncogene STAT3, are relatively frequent in HIV-DLBCL, occurring in 27% of all cases in this series, but are particularly frequent in EBV-positive HIV-DLCBL, occurring in 46% of cases. Interestingly, three recent studies also identified recurrent STAT3 mutations, leading to overexpression of phospho-STAT3 in plasmablastic lymphomas, where STAT3 mutations were seen in 42% of cases in one study, 14,15 all of which were EBV-positive. 22 Nearly all the abnormalities associated with STAT3 were seen in the SH2 domain in our series.…”