Genomic characterization of plasmablastic lymphoma identifies pervasive mutations in the JAK-STAT pathway

Plasmablastic lymphoma (PBL) is an aggressive non-Hodgkin B-cell lymphoma associated with immunodeficiency in the context of 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 pathology of this disease is poorly characterized. Here, we provide the first comprehensive genomic analysis of PBL in a cohort of 110 patients from South Africa. We identified recurrent mutations in genes of the JAK-STAT signaling pathway, including STAT3, JAK1 and SOCS1, leading to constitutive activation of this pathway. Comparative analysis with other B-cell malignancies uncovered PBL-specific somatic mutations, mutational signatures, and transcriptional programs. We also found that the stem cell like marker CD44 is highly activated, likely due to copy number gains on chromosome 11p13. This study provides the first description of the genomic landscape of PBL and identifies specific dysregulated pathways underlying its carcinogenesis.