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Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma.

ABSTRACT: Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor a MYC translocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications in MCL1 and IRF4. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients.

SUBMITTER: Frontzek F

PROVIDER: S-EPMC8408158 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Molecular and functional profiling of plasmablastic lymphoma

Project description:Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor a MYC translocation. We provide the first comprehensive integrated analysis using whole exome sequencing and copy number determination in a large cohort of primary PBL samples. We identified previously unknown alterations and high-level amplifications and characterized the functional impact of these aberrations using an unbiased shRNA screen in a PBL model. These analyses identified specific pathways as promising molecular targets to improve outcome of PBL patients.

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