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

Autor:	Closa A; The Shine-Dalgarno Centre for RNA Innovation, John Curtin School of Medical Research, Australian National University, Canberra, Australia.; Centre for Computational Biomedical Sciences, John Curtin School of Medical Research, Australian National University, Canberra, Australia.; EMBL Australia Partner Laboratory Network at the Australian National University, Canberra, Australia., Reixachs-Solé M; The Shine-Dalgarno Centre for RNA Innovation, John Curtin School of Medical Research, Australian National University, Canberra, Australia.; Centre for Computational Biomedical Sciences, John Curtin School of Medical Research, Australian National University, Canberra, Australia.; EMBL Australia Partner Laboratory Network at the Australian National University, Canberra, Australia., Fuentes-Fayos AC; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Cordoba, Spain.; University of Cordoba (UCO), Cordoba, Spain.; Reina Sofía University Hospital, Cordoba, Spain., Hayer KE; Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, USA., Melero JL; The Shine-Dalgarno Centre for RNA Innovation, John Curtin School of Medical Research, Australian National University, Canberra, Australia.; Centre for Computational Biomedical Sciences, John Curtin School of Medical Research, Australian National University, Canberra, Australia.; EMBL Australia Partner Laboratory Network at the Australian National University, Canberra, Australia., Adriaanse FRS; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands., Bos RS; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands., Torres-Diz M; Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, USA., Hunger SP; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, USA., Roberts KG; Department of Pathology, St. Jude Children's Research Hospital, Memphis, USA., Mullighan CG; Department of Pathology, St. Jude Children's Research Hospital, Memphis, USA., Stam RW; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands., Thomas-Tikhonenko A; Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, USA.; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA., Castaño JP; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Cordoba, Spain.; University of Cordoba (UCO), Cordoba, Spain.; Reina Sofía University Hospital, Cordoba, Spain.; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain., Luque RM; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Cordoba, Spain.; University of Cordoba (UCO), Cordoba, Spain.; Reina Sofía University Hospital, Cordoba, Spain.; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain., Eyras E; The Shine-Dalgarno Centre for RNA Innovation, John Curtin School of Medical Research, Australian National University, Canberra, Australia.; Centre for Computational Biomedical Sciences, John Curtin School of Medical Research, Australian National University, Canberra, Australia.; EMBL Australia Partner Laboratory Network at the Australian National University, Canberra, Australia.; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
Jazyk:	angličtina
Zdroj:	NAR cancer [NAR Cancer] 2022 Dec 09; Vol. 4 (4), pp. zcac041. Date of Electronic Publication: 2022 Dec 09 (Print Publication: 2022).
DOI:	10.1093/narcan/zcac041
Abstrakt:	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. (© The Author(s) 2022. Published by Oxford University Press on behalf of NAR Cancer.)
Databáze:	MEDLINE
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