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APRIL drives a co-ordinated but diverse response as a foundation for plasma cell longevity [I]

ABSTRACT: Antibody secreting cells (ASCs) survive in niche microenvironments, but cellular responses driven by particular niche signals are incompletely defined. The TNF superfamily (TNFSF) member A proliferation-inducing ligand (APRIL) can support the maturation of transitory plasmablasts into long-lived plasma cells. Here we explore the biological programs established by APRIL in human plasmablast. Under conditions allowing the maturation of ex vivo or in vitro generated plasmablasts, we find that APRIL drives activation of ERK, p38 and JNK, accompanied by a classical NFκB response and activation of the AKT/FOXO1 pathway. Time course gene expression data resolve co-ordinated transcriptional responses propagated via immediate early genes and NFκB targets and converging onto modules of genes enriched for MYC-targets and metabolism and cell growth related pathways. This response is shared between APRIL and an alternate TNFSF member CD40L but is not a feature of alternative niche signals delivered by IFNα or SDF1. However, APRIL and CD40L responses also diverge. CD40L drives expression of genes related to the activated B-cell state while APRIL does not. Thus, APRIL establishes a broad foundation for plasma cell longevity with features of cellular refuelling, while being uncoupled from support of the B-cell state.

ORGANISM(S): Homo sapiens

PROVIDER: GSE173644 | GEO | 2022/07/05

REPOSITORIES: GEO

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APRIL drives a co-ordinated but diverse response as a foundation for plasma cell longevity [II]

Project description:Antibody secreting cells (ASCs) survive in niche microenvironments, but cellular responses driven by particular niche signals are incompletely defined. The TNF superfamily (TNFSF) member A proliferation-inducing ligand (APRIL) can support the maturation of transitory plasmablasts into long-lived plasma cells. Here we explore the biological programs established by APRIL in human plasmablast. Under conditions allowing the maturation of ex vivo or in vitro generated plasmablasts, we find that APRIL drives activation of ERK, p38 and JNK, accompanied by a classical NFκB response and activation of the AKT/FOXO1 pathway. Time course gene expression data resolve co-ordinated transcriptional responses propagated via immediate early genes and NFκB targets and converging onto modules of genes enriched for MYC-targets and metabolism and cell growth related pathways. This response is shared between APRIL and an alternate TNFSF member CD40L but is not a feature of alternative niche signals delivered by IFNα or SDF1. However, APRIL and CD40L responses also diverge. CD40L drives expression of genes related to the activated B-cell state while APRIL does not. Thus, APRIL establishes a broad foundation for plasma cell longevity with features of cellular refuelling, while being uncoupled from support of the B-cell state.

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Project description:APRIL is involved in the development of B-cell lymphomas. However, in tumors the source of APRIL is paracrine while one signaling receptor, BCMA, is intracellular, raising the question on how APRIL may signal. In fact, tumor cells internalized APRIL via their surface HSPG. Then, APRIL trafficked into endosomes to finally interact with Golgic BCMA, whose sequence harbors strong identities with sorting nexins. Intracellular APRIL/BCMA interactions activated the canonical NF-kB pathway, and mediated from tumor cells an immunosuppressive response including IL-10 upregulation. Absence of APRIL/BCMA interactions impaired tumor growth in mice, and APRIL internalization by tumor cells correlated with a reduced survival for patients. Taken together, the present study elucidates a fully intracellular signaling pathway, key to B-cell lymphoma development.

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