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ADAR1 can drive Multiple Myeloma progression by acting both as an RNA editor of specific transcripts and as a DNA mutator of their cognate genes

View ORCID ProfileRafail Nikolaos Tasakis, Alessandro Laganà, Dimitra Stamkopoulou, David T. Melnekoff, Pavithra Nedumaran, Violetta Leshchenko, View ORCID ProfileRiccardo Pecori, Samir Parekh, F. Nina Papavasiliou
doi: https://doi.org/10.1101/2020.02.11.943845
Rafail Nikolaos Tasakis
1Division of Immune Diversity, German Cancer Research Center (DKFZ), Heidelberg, Germany
2Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany
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  • ORCID record for Rafail Nikolaos Tasakis
Alessandro Laganà
3Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
4Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Dimitra Stamkopoulou
1Division of Immune Diversity, German Cancer Research Center (DKFZ), Heidelberg, Germany
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David T. Melnekoff
3Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
4Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Pavithra Nedumaran
5Department of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Violetta Leshchenko
5Department of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Riccardo Pecori
1Division of Immune Diversity, German Cancer Research Center (DKFZ), Heidelberg, Germany
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  • ORCID record for Riccardo Pecori
Samir Parekh
5Department of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
6Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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  • For correspondence: n.papavasiliou@dkfz-heidelberg.de samir.parekh@mssm.edu
F. Nina Papavasiliou
1Division of Immune Diversity, German Cancer Research Center (DKFZ), Heidelberg, Germany
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  • For correspondence: n.papavasiliou@dkfz-heidelberg.de samir.parekh@mssm.edu
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ABSTRACT

RNA editing is an epitranscriptomic modification of emerging relevance to disease development and manifestations. ADAR1, which resides on human chromosome 1q21, is an RNA editor whose over-expression, either by interferon (IFN) induction or through gene amplification, is associated with increased editing and poor outcomes in Multiple Myeloma (MM). Here we explored the role of ADAR1 in the context of MM progression, by focusing on a group of 23 patients in the MMRF CoMMpass Study for which RNAseq and WES datasets exist for matched pre-and post-relapse samples. Our analysis reveals an acquisition of new DNA mutations on disease progression at specific loci surrounding the sites of ADAR associated (A-to-I) RNA editing. These analyses suggest that the RNA editing enzyme ADAR1 can function as a DNA mutator during Multiple Myeloma (MM) progression, and further imply that guide-targeted RNA editing has the capacity to generate specific mutational signatures at predetermined locations. This dual role of RNA editor and DNA mutator might be shared by other deaminases, such as APOBECs, so that DNA mutation might be the result of collateral damage on the genome by an editing enzyme whose primary job is to re-code the cognate transcript toward specific functional outcomes.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 21, 2020.
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ADAR1 can drive Multiple Myeloma progression by acting both as an RNA editor of specific transcripts and as a DNA mutator of their cognate genes
Rafail Nikolaos Tasakis, Alessandro Laganà, Dimitra Stamkopoulou, David T. Melnekoff, Pavithra Nedumaran, Violetta Leshchenko, Riccardo Pecori, Samir Parekh, F. Nina Papavasiliou
bioRxiv 2020.02.11.943845; doi: https://doi.org/10.1101/2020.02.11.943845
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ADAR1 can drive Multiple Myeloma progression by acting both as an RNA editor of specific transcripts and as a DNA mutator of their cognate genes
Rafail Nikolaos Tasakis, Alessandro Laganà, Dimitra Stamkopoulou, David T. Melnekoff, Pavithra Nedumaran, Violetta Leshchenko, Riccardo Pecori, Samir Parekh, F. Nina Papavasiliou
bioRxiv 2020.02.11.943845; doi: https://doi.org/10.1101/2020.02.11.943845

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