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Smith, Molly A; Choudhary, Gaurav S; Pellagatti, Andrea; Choi, Kwangmin; Bolanos, Lyndsey C; Bhagat, Tushar D; Gordon-Mitchell, Shanisha; Von Ahrens, Dagny; Pradhan, Kith; Steeples, Violetta; Kim, Sanghyun; Steidl, Ulrich; Walter, Matthew; Fraser, Iain D C; Kulkarni, Aishwarya; Salomonis, Nathan; Komurov, Kakajan; Boultwood, Jacqueline; Verma, Amit; Starczynowski, Daniel T
Nature cell biology, 05/2019, Letnik: 21, Številka: 5Journal Article
Spliceosome mutations are common in myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), but the oncogenic changes due to these mutations have not been identified. Here a global analysis of exon usage in AML samples revealed distinct molecular subsets containing alternative spliced isoforms of inflammatory and immune genes. Interleukin-1 receptor-associated kinase 4 (IRAK4) was the dominant alternatively spliced isoform in MDS and AML and is characterized by a longer isoform that retains exon 4, which encodes IRAK4-long (IRAK4-L), a protein that assembles with the myddosome, results in maximal activation of nuclear factor kappa-light-chain-enhancer of B cells (NF-κB) and is essential for leukaemic cell function. Expression of IRAK4-L is mediated by mutant U2 small nuclear RNA auxiliary factor 1 (U2AF1) and is associated with oncogenic signalling in MDS and AML. Inhibition of IRAK4-L abrogates leukaemic growth, particularly in AML cells with higher expression of the IRAK4-L isoform. Collectively, mutations in U2AF1 induce expression of therapeutically targetable 'active' IRAK4 isoforms and provide a genetic link to activation of chronic innate immune signalling in MDS and AML.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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