A convergent malignant phenotype in B-cell acute lymphoblastic leukemia involving the splicing factor SRRM1
A significant proportion of infant B-cell acute lymphoblastic leukemia (B-ALL) patients remains with a dismal prognosis due to yet undetermined mechanisms. We performed a comprehensive multicohort analysis of gene expression, gene fusions, and RNA splicing alterations to uncover molecular signatures...
| Autores: | , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:10230/56499 |
| Acceso en línea: | http://hdl.handle.net/10230/56499 http://dx.doi.org/10.1093/narcan/zcac041 |
| Access Level: | acceso abierto |
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A convergent malignant phenotype in B-cell acute lymphoblastic leukemia involving the splicing factor SRRM1Closa, AdriàReixachs i Solé, MarinaFuentes-Fayos, Antonio C.Hayer, Katharina E.Melero, Juan L.Adriaanse, Fabienne R.S.Bos, Romy S.Torres-Diz, ManuelHunger, Stephen P.Roberts, Kathryn G.Mullighan, Charles G.Stam, Ronald W.Thomas-Tikhonenko, AndreiCastaño, Justo P.Luque, Raul M.Eyras Jiménez, EduardoA significant proportion of infant B-cell acute lymphoblastic leukemia (B-ALL) patients remains with a dismal prognosis due to yet undetermined mechanisms. We performed a comprehensive multicohort analysis of gene expression, gene fusions, and RNA splicing alterations to uncover molecular signatures potentially linked to the observed poor outcome. We identified 87 fusions with significant allele frequency across patients and shared functional impacts, suggesting common mechanisms across fusions. We further identified a gene expression signature that predicts high risk independently of the gene fusion background and includes the upregulation of the splicing factor SRRM1. Experiments in B-ALL cell lines provided further evidence for the role of SRRM1 on cell survival, proliferation, and invasion. Supplementary analysis revealed that SRRM1 potentially modulates splicing events associated with poor outcomes through protein-protein interactions with other splicing factors. Our findings reveal a potential convergent mechanism of aberrant RNA processing that sustains a malignant phenotype independently of the underlying gene fusion and that could potentially complement current clinical strategies in infant B-ALL.Spanish Ministerio de Ciencia, Innovación y Universidades [BIO2017-85364-R]; EMBL Australia (to A.C., M.R-S., J.L.M., E.E.); National Institutes of Health [U01 CA232563 to A.T-T.]; M.T-D. acknowledges support from the Ellen Weisberg Fund: Advancing Breakthroughs in Pediatric Cancer. This work was further supported by the Spanish Ministry of Science and Innovation [MICINN, PID2019-105201RB-I00 to J.P.C.]; Junta de Andalucía [BIO-0139]; Universidad de Córdoba-FEDER [UCO-202099901918904 to J.P.C.]; GETNE2019 Research grant (to J.P.C.); CIBERobn Fisiopatología de la Obesidad y Nutrición (CIBER is an initiative of Instituto de Salud Carlos III, co-funded by the European Union: ERDF/ESF, ‘Investing in your future’).Oxford University Press202320232022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/56499http://dx.doi.org/10.1093/narcan/zcac041reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésNAR Cancer. 2022 Dec 9;4(4):zcac041info:eu-repo/grantAgreement/ES/2PE/BIO2017-85364-Rinfo:eu-repo/grantAgreement/ES/2PE/PID2019-105201RB-I00© The Author(s) 2022. Published by Oxford University Press on behalf of NAR Cancer. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/564992026-05-29T05:05:01Z |
| dc.title.none.fl_str_mv |
A convergent malignant phenotype in B-cell acute lymphoblastic leukemia involving the splicing factor SRRM1 |
| title |
A convergent malignant phenotype in B-cell acute lymphoblastic leukemia involving the splicing factor SRRM1 |
| spellingShingle |
A convergent malignant phenotype in B-cell acute lymphoblastic leukemia involving the splicing factor SRRM1 Closa, Adrià |
| title_short |
A convergent malignant phenotype in B-cell acute lymphoblastic leukemia involving the splicing factor SRRM1 |
| title_full |
A convergent malignant phenotype in B-cell acute lymphoblastic leukemia involving the splicing factor SRRM1 |
| title_fullStr |
A convergent malignant phenotype in B-cell acute lymphoblastic leukemia involving the splicing factor SRRM1 |
| title_full_unstemmed |
A convergent malignant phenotype in B-cell acute lymphoblastic leukemia involving the splicing factor SRRM1 |
| title_sort |
A convergent malignant phenotype in B-cell acute lymphoblastic leukemia involving the splicing factor SRRM1 |
| dc.creator.none.fl_str_mv |
Closa, Adrià Reixachs i Solé, Marina Fuentes-Fayos, Antonio C. Hayer, Katharina E. Melero, Juan L. Adriaanse, Fabienne R.S. Bos, Romy S. Torres-Diz, Manuel Hunger, Stephen P. Roberts, Kathryn G. Mullighan, Charles G. Stam, Ronald W. Thomas-Tikhonenko, Andrei Castaño, Justo P. Luque, Raul M. Eyras Jiménez, Eduardo |
| author |
Closa, Adrià |
| author_facet |
Closa, Adrià Reixachs i Solé, Marina Fuentes-Fayos, Antonio C. Hayer, Katharina E. Melero, Juan L. Adriaanse, Fabienne R.S. Bos, Romy S. Torres-Diz, Manuel Hunger, Stephen P. Roberts, Kathryn G. Mullighan, Charles G. Stam, Ronald W. Thomas-Tikhonenko, Andrei Castaño, Justo P. Luque, Raul M. Eyras Jiménez, Eduardo |
| author_role |
author |
| author2 |
Reixachs i Solé, Marina Fuentes-Fayos, Antonio C. Hayer, Katharina E. Melero, Juan L. Adriaanse, Fabienne R.S. Bos, Romy S. Torres-Diz, Manuel Hunger, Stephen P. Roberts, Kathryn G. Mullighan, Charles G. Stam, Ronald W. Thomas-Tikhonenko, Andrei Castaño, Justo P. Luque, Raul M. Eyras Jiménez, Eduardo |
| author2_role |
author author author author author author author author author author author author author author author |
| description |
A significant proportion of infant B-cell acute lymphoblastic leukemia (B-ALL) patients remains with a dismal prognosis due to yet undetermined mechanisms. We performed a comprehensive multicohort analysis of gene expression, gene fusions, and RNA splicing alterations to uncover molecular signatures potentially linked to the observed poor outcome. We identified 87 fusions with significant allele frequency across patients and shared functional impacts, suggesting common mechanisms across fusions. We further identified a gene expression signature that predicts high risk independently of the gene fusion background and includes the upregulation of the splicing factor SRRM1. Experiments in B-ALL cell lines provided further evidence for the role of SRRM1 on cell survival, proliferation, and invasion. Supplementary analysis revealed that SRRM1 potentially modulates splicing events associated with poor outcomes through protein-protein interactions with other splicing factors. Our findings reveal a potential convergent mechanism of aberrant RNA processing that sustains a malignant phenotype independently of the underlying gene fusion and that could potentially complement current clinical strategies in infant B-ALL. |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2022 2023 2023 |
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info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10230/56499 http://dx.doi.org/10.1093/narcan/zcac041 |
| url |
http://hdl.handle.net/10230/56499 http://dx.doi.org/10.1093/narcan/zcac041 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
NAR Cancer. 2022 Dec 9;4(4):zcac041 info:eu-repo/grantAgreement/ES/2PE/BIO2017-85364-R info:eu-repo/grantAgreement/ES/2PE/PID2019-105201RB-I00 |
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http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess |
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http://creativecommons.org/licenses/by/4.0/ |
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openAccess |
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application/pdf application/pdf |
| dc.publisher.none.fl_str_mv |
Oxford University Press |
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Oxford University Press |
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reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Recercat. Dipósit de la Recerca de Catalunya |
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Recercat. Dipósit de la Recerca de Catalunya |
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