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DYRK1A Regulates Alternative Splicing in B-ALL
John Crispino1, Qi Jin1, Ethan Harris1, Jacqueline Myers1, Sebastien Malinge2, and Esther Obeng11 St. Jude Children’s Research Hospital, Memphis, TN, USA
2 Telethon Kids’ Institute, Perth, Australia
Children with Down syndrome (DS) are at a 20-fold increased risk of developing B-cell acute lymphoblastic leukemia (DS-ALL). Many of these cases show CRLF2 overexpression and JAK2 mutations, which are associated with a poor prognosis in B-ALL in children without DS. Indeed, outcomes for DS-ALL are worse than those of children without DS. In our efforts to identify drivers of DS-ALL, we have focused on a handful of genes in the DS critical region, including dual-specificity tyrosine phosphorylation–regulated kinase 1A (DYRK1A). We recently demonstrated that DYRK1A is essential for B and T cell development and is a therapeutic target in B-ALL. Critical DYRK1A substrates in lymphocytes include cyclin D3, FOXO1, and STAT3. In more recent work, we have examined the link between DYRK1A and alternative splicing, as DYRK1A has been reported to phosphorylate numerous splicing factors including SF3B1 and SRSF2. We discovered that DYRK1A regulates alternative splicing of many genes, with enrichment of alternative splicing factors that represent potential new therapeutic targets. Results from these studies in DS-ALL and high-risk B-ALL will be presented.
Speakers
John Crispino