RNA splicing links segments of messenger RNA into a “complete” template for protein synthesis and is regulated by proteins called splicing factors. Splicing-factor mutations can cause the blood diseases myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how those mutations caused disease wasn’t known. In a study published online on April 22 in Nature Cell Biology, co-first author Gaurav Choudhary, Ph.D., co-corresponding author, Amit K. Verma, M.B.B.S., and their team showed that a splicing-factor mutation triggers formation of the protein IRAK4-L (an active form of the protein IRAK4), which leads to MDS/AML. The researchers also found that IRAK4-L’s expression in MDS/AML is mediated by the mutated U2AF1 splicing factor. IRAK4-L inhibitors suppressed leukemic growth of AML cells—a strategy that worked even better when the cells had U2AF1 mutations, indicating that U2AF1 mutations make IRAK4-L more targetable. IRAK4 inhibitors will soon be tested in MDS clinical trials. Dr. Verma is professor of medicine and of developmental and molecular biology at Einstein and attending physician in oncology at Montefiore Einstein Center for Cancer Care. The research was co-led by Daniel Starczynowski, Ph.D., of Cincinnati Children’s Hospital and Jacqueline Boultwood, Ph.D., of the University of Oxford.
Posted on: Tuesday, May 28, 2019