Research Papers:

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 and Antonino Neri _

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Oncotarget. 2015; 6:26129-26141. https://doi.org/10.18632/oncotarget.4674

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Marta Lionetti1,2*, Marzia Barbieri2*, Katia Todoerti3, Luca Agnelli1,2, Sonia Fabris2, Giovanni Tonon4, Simona Segalla4, Ingrid Cifola5, Eva Pinatel5, Pierfrancesco Tassone6, Pellegrino Musto3, Luca Baldini1,2 and Antonino Neri1,2

1Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy

2Hematology Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy

3Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture (PZ), Italy

4Functional Genomics of Cancer Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy

5Institute for Biomedical Technologies, National Research Council, Milan, Italy

6Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy

*These authors have contributed equally to this work

Correspondence to:

Antonino Neri, e-mail: [email protected]

Marta Lionetti, e-mail: [email protected]

Keywords: multiple myeloma, plasma cell leukemia, DIS3, next-generation sequencing

Received: May 08, 2015     Accepted: July 06, 2015     Published: July 20, 2015


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.

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