Aberrant splicing in B-cell acute lymphoblastic leukemia.
Nucleic Acids Res
; 46(21): 11357-11369, 2018 11 30.
Article
em En
| MEDLINE
| ID: mdl-30357359
ABSTRACT
Aberrant splicing is a hallmark of leukemias with mutations in splicing factor (SF)-encoding genes. Here we investigated its prevalence in pediatric B-cell acute lymphoblastic leukemias (B-ALL), where SFs are not mutated. By comparing these samples to normal pro-B cells, we found thousands of aberrant local splice variations (LSVs) per sample, with 279 LSVs in 241 genes present in every comparison. These genes were enriched in RNA processing pathways and encoded â¼100 SFs, e.g. hnRNPA1. HNRNPA1 3'UTR was most pervasively mis-spliced, yielding the transcript subject to nonsense-mediated decay. To mimic this event, we knocked it down in B-lymphoblastoid cells and identified 213 hnRNPA1-regulated exon usage events comprising the hnRNPA1 splicing signature in pediatric leukemia. Some of its elements were LSVs in DICER1 and NT5C2, known cancer drivers. We searched for LSVs in other leukemia and lymphoma drivers and discovered 81 LSVs in 41 additional genes. Seventy-seven LSVs out of 81 were confirmed using two large independent B-ALL RNA-seq datasets, and the twenty most common B-ALL drivers, including NT5C2, showed higher prevalence of aberrant splicing than of somatic mutations. Thus, post-transcriptional deregulation of SF can drive widespread changes in B-ALL splicing and likely contributes to disease pathogenesis.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Linfócitos B
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Regulação Leucêmica da Expressão Gênica
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Processamento Alternativo
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Leucemia-Linfoma Linfoblástico de Células Precursoras
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Degradação do RNAm Mediada por Códon sem Sentido
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Ribonucleoproteína Nuclear Heterogênea A1
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Adult
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Child
/
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article