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<p>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 <i>IGH</i> 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.</p>

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DIS3 mutations enhance AID-driven translocations during B-cell activation, promoting transformation to multiple myeloma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月14日

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  • Tomasz M. Kuliński,
  • Olga Gewartowska,
  • Mélanie Mahé,
  • Karolina Kasztelan,
  • Nina Durys,
  • Anna Stroynowska-Czerwińska,
  • Marta Jedynak-Slyvka,
  • Ewelina P. Owczarek,
  • Debadeep Chaudhury,
  • Marcin Nowotny,
  • Aleksandra Pękowska,
  • Bertrand Séraphin,
  • Andrzej Dziembowski

摘要

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.