Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1784882452058079232 |
---|---|
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. |
format | Online Article Text |
id | pubmed-9898564 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT ogiyadaisuke identificationofdiseaserelatedaberrantlysplicedtranscriptsinmyelomaandstrategiestotargetthesealterationsbyrnabasedtherapeutics AT chyrazuzana identificationofdiseaserelatedaberrantlysplicedtranscriptsinmyelomaandstrategiestotargetthesealterationsbyrnabasedtherapeutics AT verselissigitasj identificationofdiseaserelatedaberrantlysplicedtranscriptsinmyelomaandstrategiestotargetthesealterationsbyrnabasedtherapeutics AT okeefemorgan identificationofdiseaserelatedaberrantlysplicedtranscriptsinmyelomaandstrategiestotargetthesealterationsbyrnabasedtherapeutics AT cobbjacquelyn identificationofdiseaserelatedaberrantlysplicedtranscriptsinmyelomaandstrategiestotargetthesealterationsbyrnabasedtherapeutics AT abiatariivane identificationofdiseaserelatedaberrantlysplicedtranscriptsinmyelomaandstrategiestotargetthesealterationsbyrnabasedtherapeutics AT tallurisrikanth identificationofdiseaserelatedaberrantlysplicedtranscriptsinmyelomaandstrategiestotargetthesealterationsbyrnabasedtherapeutics AT sitharaanjanaanilkumar identificationofdiseaserelatedaberrantlysplicedtranscriptsinmyelomaandstrategiestotargetthesealterationsbyrnabasedtherapeutics AT hideshimateru identificationofdiseaserelatedaberrantlysplicedtranscriptsinmyelomaandstrategiestotargetthesealterationsbyrnabasedtherapeutics AT chumichaelp identificationofdiseaserelatedaberrantlysplicedtranscriptsinmyelomaandstrategiestotargetthesealterationsbyrnabasedtherapeutics AT hajekroman identificationofdiseaserelatedaberrantlysplicedtranscriptsinmyelomaandstrategiestotargetthesealterationsbyrnabasedtherapeutics AT dorfmandavidm identificationofdiseaserelatedaberrantlysplicedtranscriptsinmyelomaandstrategiestotargetthesealterationsbyrnabasedtherapeutics AT pilarskilindam identificationofdiseaserelatedaberrantlysplicedtranscriptsinmyelomaandstrategiestotargetthesealterationsbyrnabasedtherapeutics AT andersonkennethc identificationofdiseaserelatedaberrantlysplicedtranscriptsinmyelomaandstrategiestotargetthesealterationsbyrnabasedtherapeutics AT adamiasophia identificationofdiseaserelatedaberrantlysplicedtranscriptsinmyelomaandstrategiestotargetthesealterationsbyrnabasedtherapeutics |