Abstract
DIS3, a key nuclear RNA-degrading enzyme, is essential for immunoglobulin class switch recombination (CSR), promoting activation-induced cytidine deaminase (AID) activity on both DNA strands to induce double-strand DNA breaks. During somatic hypermutation, AID-dependent lesions predominantly occur on the non-template DNA strand. Dominant mutations impairing DIS3 exoribonucleolytic activity are common in multiple myeloma (MM), but their role in carcinogenesis remains unclear. Here we show, using a knock-in mouse model, that the clinically relevant DIS3 G766R variant causes chromosomal translocations in B-cells, characterized by aberrant AID activity signatures. The mice develop pristane-induced plasmacytomas, modeling early-stage MM. In clinical MM samples, DIS3 mutations correlate with IGH translocations and AID-driven lesions in driver genes. Mechanistically, mutated DIS3 accumulates on chromatin-bound RNA, particularly at aberrant AID target sites, promoting mutations on both DNA strands. This results in increased AID-dependent double-strand DNA breaks, fostering microhomology-mediated oncogenic rearrangements. Translocations occur specifically during CSR, which remains functionally intact. The DIS3 G766R mutation does not disrupt chromatin architecture in activated B cells but exploits spatial proximity to permanently juxtapose enhancers and proto-oncogenes, facilitating transformation. Thus, gain-of-function DIS3 mutations enhance AID promiscuity, driving IGH translocations and MM development without broadly affecting B-cell physiology.
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Data availability
The sequencing data have been deposited in NCBI’s Gene Expression Omnibus (GEO) under the accession code GSE155631. The raw sequencing data have been deposited in the Sequence Read Archive (SRA) under the accession code SRP275679, associated with BioProject PRJNA650522. The mass spectrometry proteomics data have been deposited in the ProteomeXchange Consortium via the PRIDE repository under the accession code PXD050438. Source data are provided with this paper.
Code availability
All custom scripts used for analyses have been deposited in Mendeley Data and are publicly available at: 10.17632/7tdgwkzmnr.1.
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Acknowledgements
We thank Justyna Chlebowska, Jakub Gruchota, Kamila Kłosowska-Kosicka, Dorota Adamska, Michał Kamiński, Radosław Salamon, Katarzyna Prokop, and Monika Kusio-Kobiałka for help with selected experiments, Maria Anna Ciemerych-Litwinienko, Dominika Nowis, Jakub Gołąb, Joanna Kufel, Katarzyna Matylla-Kulińska for attentive readings of the manuscript and all Andrzej Dziembowski lab members for fruitful discussions. We thank the expert support of the Mouse Clinic Institute (Illkirch) in mouse construction and handling. Efforts of the MM Research Foundation (MMRF) and centers that contributed to the CoMMpass study are also acknowledged. All mice lines were genotyped by the Genome Engineering Facility (GEF), part of IIMCB IN-MOL-CELL Infrastructure (RRID: SCR_021630) funded by the European Union – NextGenerationEU under National Recovery and Resilience Plan, Horizon Europe (Project 101059801 - RACE) and RACE-PRIME project carried out within the IRAP program of the Foundation for Polish Science co-financed by the European Union under the European Funds for Smart Economy 2021-2027 (FENG) IIMCB. This work was mainly supported by grant funding from the National Science Center (NCN) to AD (UMO-2016/22/A/NZ4/00380; UMO-2013/10/M/NZ4/00299) and TK (UMO-2019/32/C/NZ2/00558). This research was co-supported by funding from the European Union’s Horizon 2020 research and innovation program (grant agreement no. 810425). Work in BS laboratory was supported by INCA PRTK 2021-025, USIAS, ANR-10-IDEX-0002, ANR 20-SFRI-0012, ANR-17-EURE-0023. Work in the AP laboratory is funded by the Dioscuri Grant [Dioscuri is a program initiated by the Max Planck Society (MPG), jointly managed with the National Science Center in Poland (NCN), and mutually funded by the Polish Ministry of Education and Science and the German Federal Ministry of Education and Research (BMBF)]; by the OPUS17 (UMO-2019/33/B/NZ2/02437), OPUS22 (UMO-2021/43/B/NZ2/02934), and Sonata Bis 11 (UMO-2021/42/E/NZ2/00392) grants from the NCN; and by the EMBO Installation Grant.
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T.K.: conceptualization, all bioinformatic analysis, and experimental work; O.G., M.M., N.D., K.K., A.S.C., M.J.S., E.P.O., and M.N.: experimental work; A.P. and D.C.: bioinformatic analysis B.S.: conceptualization and knock-in mice; AD: conceptualization, supervision, original draft preparation.
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Kuliński, T.M., Gewartowska, O., Mahé, M. et al. DIS3 mutations enhance AID-driven translocations during B-cell activation, promoting transformation to multiple myeloma. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70386-3
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DOI: https://doi.org/10.1038/s41467-026-70386-3
