A compendium of DIS3 mutations and associated transcriptional signatures in plasma cell dyscrasias

Marta Lionetti, Marzia Barbieri, Katia Todoerti, Luca Agnelli, Sonia Fabris, Giovanni Tonon, Simona Segalla, Ingrid Cifola, Eva Pinatel, Pierfrancesco Tassone, Pellegrino Musto, Luca Baldini, Antonino Neri

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

DIS3 is a catalytic subunit of the human exosome complex, containing exonucleolytic (RNB) and endonucleolytic (PIN) domains, recently found mutated in multiple myeloma (MM), a clinically and genetically heterogeneous form of plasma cell (PC) dyscrasia. We analyzed by next-generation sequencing (NGS) the DIS3 PIN and RNB domains in purified bone marrow PCs from 164 representative patients, including 130 cases with MM, 24 with primary PC leukemia and 10 with secondary PC leukemia. DIS3 mutations were found respectively in 18.5%, 25% and 30% of cases. Identified variants were predominantly missense mutations localized in the RNB domain, and were often detected at low allele frequency. DIS3 mutations were preferentially carried by IGH-translocated/nonhyperdiploid patients. Sequential analysis at diagnosis and relapse in a subset of cases highlighted some instances of increasing DIS3 mutation burden during disease progression. NGS also revealed that the majority of DIS3 variants in mutated cases were comparably detectable at transcriptional level. Furthermore, gene expression profiling analysis in DIS3-mutated patients identified a transcriptional signature suggestive for impaired RNA exosome function. In conclusion, these data further support the pathological relevance of DIS3 mutations in plasma cell dyscrasias and suggest that DIS3 may represent a potential tumor suppressor gene in such disorders.

Original languageEnglish
Pages (from-to)26129-26141
Number of pages13
JournalOncotarget
Volume6
Issue number28
DOIs
Publication statusPublished - 2015

Fingerprint

Paraproteinemias
Plasma Cell Leukemia
Mutation
Multiple Myeloma
Exosome Multienzyme Ribonuclease Complex
Exosomes
Patient Advocacy
Gene Expression Profiling
Missense Mutation
Tumor Suppressor Genes
Gene Frequency
Disease Progression
Catalytic Domain
Bone Marrow
Recurrence

Keywords

  • DIS3
  • Multiple myeloma
  • Next-generation sequencing
  • Plasma cell leukemia

ASJC Scopus subject areas

  • Oncology

Cite this

A compendium of DIS3 mutations and associated transcriptional signatures in plasma cell dyscrasias. / Lionetti, Marta; Barbieri, Marzia; Todoerti, Katia; Agnelli, Luca; Fabris, Sonia; Tonon, Giovanni; Segalla, Simona; Cifola, Ingrid; Pinatel, Eva; Tassone, Pierfrancesco; Musto, Pellegrino; Baldini, Luca; Neri, Antonino.

In: Oncotarget, Vol. 6, No. 28, 2015, p. 26129-26141.

Research output: Contribution to journalArticle

Lionetti, Marta ; Barbieri, Marzia ; Todoerti, Katia ; Agnelli, Luca ; Fabris, Sonia ; Tonon, Giovanni ; Segalla, Simona ; Cifola, Ingrid ; Pinatel, Eva ; Tassone, Pierfrancesco ; Musto, Pellegrino ; Baldini, Luca ; Neri, Antonino. / A compendium of DIS3 mutations and associated transcriptional signatures in plasma cell dyscrasias. In: Oncotarget. 2015 ; Vol. 6, No. 28. pp. 26129-26141.
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