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 ∼100 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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3' Untranslated Regions
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5'-Nucleotidase / genetics
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5'-Nucleotidase / metabolism
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Adult
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Alternative Splicing*
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B-Lymphocytes / metabolism*
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B-Lymphocytes / pathology
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Bone Marrow Cells / metabolism
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Bone Marrow Cells / pathology
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Cell Line, Tumor
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Child
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DEAD-box RNA Helicases / genetics
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DEAD-box RNA Helicases / metabolism
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Exons
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Gene Expression Regulation, Leukemic*
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Heterogeneous Nuclear Ribonucleoprotein A1 / genetics*
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Heterogeneous Nuclear Ribonucleoprotein A1 / metabolism
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Humans
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Introns
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Nonsense Mediated mRNA Decay*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Primary Cell Culture
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RNA Helicases / genetics
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RNA Helicases / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Ribonuclease III / genetics
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Ribonuclease III / metabolism
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Serine-Arginine Splicing Factors / antagonists & inhibitors
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Serine-Arginine Splicing Factors / genetics
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Serine-Arginine Splicing Factors / metabolism
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Trans-Activators / genetics
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Trans-Activators / metabolism
Substances
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3' Untranslated Regions
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Heterogeneous Nuclear Ribonucleoprotein A1
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RNA, Small Interfering
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SRSF3 protein, human
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Trans-Activators
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hnRNPA1 protein, human
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Serine-Arginine Splicing Factors
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DICER1 protein, human
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Ribonuclease III
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5'-Nucleotidase
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NT5C2 protein, human
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DEAD-box RNA Helicases
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RNA Helicases
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UPF1 protein, human