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Identification of disease-related aberrantly spliced transcripts in myeloma and strategies to target these alterations by RNA-based therapeutics

Novel drug discoveries have shifted the treatment paradigms of most hematological malignancies, including multiple myeloma (MM). However, this plasma cell malignancy remains incurable, and novel therapies are therefore urgently needed. Whole-genome transcriptome analyses in a large cohort of MM pati...

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Autores principales: Ogiya, Daisuke, Chyra, Zuzana, Verselis, Sigitas J., O’Keefe, Morgan, Cobb, Jacquelyn, Abiatari, Ivane, Talluri, Srikanth, Sithara, Anjana Anilkumar, Hideshima, Teru, Chu, Michael P., Hájek, Roman, Dorfman, David M., Pilarski, Linda M., Anderson, Kenneth C., Adamia, Sophia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9898564/
https://www.ncbi.nlm.nih.gov/pubmed/36737429
http://dx.doi.org/10.1038/s41408-023-00791-0
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author Ogiya, Daisuke
Chyra, Zuzana
Verselis, Sigitas J.
O’Keefe, Morgan
Cobb, Jacquelyn
Abiatari, Ivane
Talluri, Srikanth
Sithara, Anjana Anilkumar
Hideshima, Teru
Chu, Michael P.
Hájek, Roman
Dorfman, David M.
Pilarski, Linda M.
Anderson, Kenneth C.
Adamia, Sophia
author_facet Ogiya, Daisuke
Chyra, Zuzana
Verselis, Sigitas J.
O’Keefe, Morgan
Cobb, Jacquelyn
Abiatari, Ivane
Talluri, Srikanth
Sithara, Anjana Anilkumar
Hideshima, Teru
Chu, Michael P.
Hájek, Roman
Dorfman, David M.
Pilarski, Linda M.
Anderson, Kenneth C.
Adamia, Sophia
author_sort Ogiya, Daisuke
collection PubMed
description Novel drug discoveries have shifted the treatment paradigms of most hematological malignancies, including multiple myeloma (MM). However, this plasma cell malignancy remains incurable, and novel therapies are therefore urgently needed. Whole-genome transcriptome analyses in a large cohort of MM patients demonstrated that alterations in pre-mRNA splicing (AS) are frequent in MM. This manuscript describes approaches to identify disease-specific alterations in MM and proposes RNA-based therapeutic strategies to eradicate such alterations. As a “proof of concept”, we examined the causes of aberrant HMMR (Hyaluronan-mediated motility receptor) splicing in MM. We identified clusters of single nucleotide variations (SNVs) in the HMMR transcript where the altered splicing took place. Using bioinformatics tools, we predicted SNVs and splicing factors that potentially contribute to aberrant HMMR splicing. Based on bioinformatic analyses and validation studies, we provided the rationale for RNA-based therapeutic strategies to selectively inhibit altered HMMR splicing in MM. Since splicing is a hallmark of many cancers, strategies described herein for target identification and the design of RNA-based therapeutics that inhibit gene splicing can be applied not only to other genes in MM but also more broadly to other hematological malignancies and solid tumors as well.
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spelling pubmed-98985642023-02-05 Identification of disease-related aberrantly spliced transcripts in myeloma and strategies to target these alterations by RNA-based therapeutics Ogiya, Daisuke Chyra, Zuzana Verselis, Sigitas J. O’Keefe, Morgan Cobb, Jacquelyn Abiatari, Ivane Talluri, Srikanth Sithara, Anjana Anilkumar Hideshima, Teru Chu, Michael P. Hájek, Roman Dorfman, David M. Pilarski, Linda M. Anderson, Kenneth C. Adamia, Sophia Blood Cancer J Article Novel drug discoveries have shifted the treatment paradigms of most hematological malignancies, including multiple myeloma (MM). However, this plasma cell malignancy remains incurable, and novel therapies are therefore urgently needed. Whole-genome transcriptome analyses in a large cohort of MM patients demonstrated that alterations in pre-mRNA splicing (AS) are frequent in MM. This manuscript describes approaches to identify disease-specific alterations in MM and proposes RNA-based therapeutic strategies to eradicate such alterations. As a “proof of concept”, we examined the causes of aberrant HMMR (Hyaluronan-mediated motility receptor) splicing in MM. We identified clusters of single nucleotide variations (SNVs) in the HMMR transcript where the altered splicing took place. Using bioinformatics tools, we predicted SNVs and splicing factors that potentially contribute to aberrant HMMR splicing. Based on bioinformatic analyses and validation studies, we provided the rationale for RNA-based therapeutic strategies to selectively inhibit altered HMMR splicing in MM. Since splicing is a hallmark of many cancers, strategies described herein for target identification and the design of RNA-based therapeutics that inhibit gene splicing can be applied not only to other genes in MM but also more broadly to other hematological malignancies and solid tumors as well. Nature Publishing Group UK 2023-02-03 /pmc/articles/PMC9898564/ /pubmed/36737429 http://dx.doi.org/10.1038/s41408-023-00791-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Ogiya, Daisuke
Chyra, Zuzana
Verselis, Sigitas J.
O’Keefe, Morgan
Cobb, Jacquelyn
Abiatari, Ivane
Talluri, Srikanth
Sithara, Anjana Anilkumar
Hideshima, Teru
Chu, Michael P.
Hájek, Roman
Dorfman, David M.
Pilarski, Linda M.
Anderson, Kenneth C.
Adamia, Sophia
Identification of disease-related aberrantly spliced transcripts in myeloma and strategies to target these alterations by RNA-based therapeutics
title Identification of disease-related aberrantly spliced transcripts in myeloma and strategies to target these alterations by RNA-based therapeutics
title_full Identification of disease-related aberrantly spliced transcripts in myeloma and strategies to target these alterations by RNA-based therapeutics
title_fullStr Identification of disease-related aberrantly spliced transcripts in myeloma and strategies to target these alterations by RNA-based therapeutics
title_full_unstemmed Identification of disease-related aberrantly spliced transcripts in myeloma and strategies to target these alterations by RNA-based therapeutics
title_short Identification of disease-related aberrantly spliced transcripts in myeloma and strategies to target these alterations by RNA-based therapeutics
title_sort identification of disease-related aberrantly spliced transcripts in myeloma and strategies to target these alterations by rna-based therapeutics
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9898564/
https://www.ncbi.nlm.nih.gov/pubmed/36737429
http://dx.doi.org/10.1038/s41408-023-00791-0
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