Biopolym. Cell. 2019; 35(3):191-192.
Хроніка та інформація
Dysregulation of splicing factors in B-cell acute lymphoblastic leukemia
1Томас-Тихоненко А.
  1. Division of Cancer Pathobiology of the Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania
    Philadelphia, PA 19104, USA


Aberrant splicing is a hallmark of leukemias with mutations in splicing factor (SF)-encoding genes. We investigated its prevalence in pediatric B-cell acute lymphoblastic leukemias (B-ALL), where SFs are not mutated. By comparing them 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-dependent aberrant exon usage events comprising the hnRNPA1 splicing signature in pediatric leukemia. Some of its elements were LSVs in DICER1 and NT5C2, known cancer genes. More broadly, 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.