DIS3 licenses B cells for plasma cell differentiation in humans
DIS3 is the main catalytic subunit of the nuclear RNA exosome, a complex playing a crucial role in RNA processing and the degradation of various noncoding RNA substrates. In mice, DIS3 is essential for genomic rearrangements during B cell development, but its role in terminal plasma cell (PC) differentiation has not been explored. Although DIS3 gene alterations are frequent in multiple myeloma (MM), a PC malignancy, their molecular impact remains poorly understood. In this study, we developed an antisense oligonucleotide strategy to knock down DIS3 expression in a well-characterized model of human PC differentiation. Reducing DIS3 expression systematically led to decreased B cell proliferation and impaired PC differentiation with lower levels of switched immunoglobulin secretion. Transcriptome analyses confirmed alterations in the proliferation and differentiation programs, alongside an accumulation of noncoding RNAs. Notably, centromere-associated noncoding RNAs were highly sensitive to DIS3 activity, and their accumulation in DIS3-deficient cells, either as transcripts or DNA-associated RNAs, correlated with the mislocalization of the centromere-specific histone variant CENP-A. We finally observed reduced physiological DNA recombination and somatic hypermutation but increased genomic instability in DIS3-deficient cells, in agreement with the higher levels of IGH translocations observed in our large cohort of DIS3-mutant MM patients. Together, these results underscore the essential role of DIS3 in regulating B cell proliferation, DNA recombination, and physiological or malignant PC differentiation in humans.
Authors
- Anaïs Schavgoulidze (ORCID: https://orcid.org/0000-0002-5526-4279)
- Charles Dumontet (ORCID: https://orcid.org/0000-0003-1875-134X)
- Laurent Delpy (ORCID: https://orcid.org/0000-0002-9480-8515)
- Céline Monvoisin (ORCID: https://orcid.org/0000-0003-1511-7888)
- Mireille Bouchet
- Brice Laffleur (ORCID: https://orcid.org/0000-0003-2904-9345)
- Jérôme Moreaux (ORCID: https://orcid.org/0000-0002-5717-3207)
- Laurent Deleurme
- Jill Corre (ORCID: https://orcid.org/0000-0003-1580-6106)
- Michel Cogné (ORCID: https://orcid.org/0000-0002-8519-4427)
- Steve Genebrier (ORCID: https://orcid.org/0000-0002-6353-5497)
- Maïwenn Pineau (ORCID: https://orcid.org/0000-0002-3535-148X)
- Simon Léonard (ORCID: https://orcid.org/0000-0002-6437-5800)
- Delfina Ordanoska
- Emma Miglierina
- M. Le Goff
- Laure Derrier
- Gwenaëlle Quéré
- Julien Bouder
- Samuel Bastos Serra Trinca
Institutions
- Université Claude Bernard Lyon 1 (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Lyon College (US)
- Université Rennes 2 (FR)
- Centre de Recherche en Neurosciences de Lyon (FR)
- Institut universitaire du cancer de Toulouse Oncopole (FR)
- Centre de Recherche en Cancérologie de Lyon (FR)
- Contrôle de la Réponse Immune B et Lymphoproliférations (FR)
- Centre Hospitalier Universitaire de Rennes (FR)
- Institut de Génétique Humaine (FR)
- Microenvironment and B-cells: Immunopathology, Cell, Differentiation and Cancer (FR)
- Université de Rennes (FR)
- Université de Limoges (FR)
Publication Details
- Journal
- Cellular and Molecular Immunology
- Published
- 2025-11-25
- DOI
- https://doi.org/10.1038/s41423-025-01369-5
- Primary Topic
- PI3K/AKT/mTOR signaling in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Association pour la Recherche sur le Cancer
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Ligue Contre le Cancer
- Institut National Du Cancer
- Région Bretagne