A convergent malignant phenotype in B-cell acute lymphoblastic leukemia involving the splicing factor SRRM1

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  • dc.contributor.author Closa, Adrià
  • dc.contributor.author Reixachs-Solé, Marina
  • dc.contributor.author Fuentes-Fayos, Antonio C.
  • dc.contributor.author Hayer, Katharina E.
  • dc.contributor.author Melero, Juan L.
  • dc.contributor.author Adriaanse, Fabienne R.S.
  • dc.contributor.author Bos, Romy S.
  • dc.contributor.author Torres-Diz, Manuel
  • dc.contributor.author Hunger, Stephen P.
  • dc.contributor.author Roberts, Kathryn G.
  • dc.contributor.author Mullighan, Charles G.
  • dc.contributor.author Stam, Ronald W.
  • dc.contributor.author Thomas-Tikhonenko, Andrei
  • dc.contributor.author Castaño, Justo P.
  • dc.contributor.author Luque, Raul M.
  • dc.contributor.author Eyras Jiménez, Eduardo
  • dc.date.accessioned 2023-04-19T11:41:26Z
  • dc.date.available 2023-04-19T11:41:26Z
  • dc.date.issued 2022
  • dc.description.abstract 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.
  • dc.description.sponsorship 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’).
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Closa A, Reixachs-Solé M, Fuentes-Fayos AC, Hayer KE, Melero JL, Adriaanse FRS, Bos RS, Torres-Diz M, Hunger SP, Roberts KG, Mullighan CG, Stam RW, Thomas-Tikhonenko A, Castaño JP, Luque RM, Eyras E. A convergent malignant phenotype in B-cell acute lymphoblastic leukemia involving the splicing factor SRRM1. NAR Cancer. 2022 Dec 9;4(4):zcac041. DOI: 10.1093/narcan/zcac041
  • dc.identifier.doi http://dx.doi.org/10.1093/narcan/zcac041
  • dc.identifier.issn 2632-8674
  • dc.identifier.uri http://hdl.handle.net/10230/56499
  • dc.language.iso eng
  • dc.publisher Oxford University Press
  • dc.relation.ispartof NAR Cancer. 2022 Dec 9;4(4):zcac041
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BIO2017-85364-R
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-105201RB-I00
  • dc.rights © 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.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.title A convergent malignant phenotype in B-cell acute lymphoblastic leukemia involving the splicing factor SRRM1
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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