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.

High Metabolic Dependence on Oxidative Phosphorylation Drives Sensitivity to Metformin Treatment in MLL/AF9 Acute Myeloid Leukemia

“…The virus supernatants were collected and filtered through 0.45 µM filters at 48 h and 72 h post-transfection. Murine HPCs or K452TRBSR cells were transduced with retrovirus encoding pMIG or MLL/AF9 by spin infection using polybrene (8 µg/mL, Sigma-Aldrich) as a transfection reagent [13,17]. All GFP+ cells were sorted by flow cytometry at 48 h after transduction for the experiments.…”

“…Immunoblot was performed according to standard procedures [14,17]. Briefly, proteins were extracted from cells with PhosphoSafe Extraction Reagent (Merck KGaA, Darmstadt, Germany) and quantified using bicinchoninic acid assay (Thermo Scientific, Hennigsdorf, Germany).…”

Clinical and Therapeutic Implications of Epstein–Barr Virus in HIV-Related Lymphomas

“…Nevertheless, recent studies have revealed that dysregulating mutations in the JAK-STAT and RAS-MAPK pathways are genetic signatures of PBL. These mutations mostly affect STAT3 , TP53 , and RAS family members, and with less frequency affect MYC , EP300 , CARD11 , SOCS1 , and TET2 [ 116 , 117 , 118 , 119 ]. Additionally, MYC translocation is the most frequent genetic alteration found [ 114 , 120 , 121 ], being more frequent in HIV-related PBL than in PBL in the general population (78% vs. 44%).…”

“…Additionally, some studies describe different genetic alterations depending on the EBV status. Mutations in TP53 are more frequent among EBV-negative compared with EBV-positive PBL [ 116 , 117 ], while mutations in STAT3 and SOCS1 are more common in EBV-positive cases [ 116 ]. Garcia-Reyero et al reported that EBV-related PBL cases presented greater genomic stability than EBV-negative cases (87.5% vs. 54%), as well as a different mutational profile [ 118 ].…”

Genome Instability in Multiple Myeloma: Facts and Factors

“…For instance, the mutational landscapes of MM, plasmablastic lymphoma (PBL), and diffuse large B-cell lymphoma (DLBCL) differ in the proportion of mutations affecting the signaling pathways RAS/MAPK, JAK/STAT, and NOTCH. Another remarkable feature is different frequencies of mutations affecting DIS3 and TET2 genes [ 716 , 717 , 718 ].…”