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

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

doi:http://dx.doi.org/10.1093/narcan/zcac041

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

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

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.