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...

Descripción completa

Detalles Bibliográficos
Autores: 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
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
Descripción
Sumario: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.

Similares en LA Referencia