U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies

Molly A. Smith, Gaurav S. Choudhary, Andrea Pellagatti, Kwangmin Choi, Lyndsey C. Bolanos, Tushar D. Bhagat, Shanisha Gordon-Mitchell, Dagny Von Ahrens, Kith Pradhan, Violetta Steeples, Sanghyun Kim, Ulrich Steidl, Matthew Walter, Iain D.C. Fraser, Aishwarya Kulkarni, Nathan Salomonis, Kakajan Komurov, Jacqueline Boultwood, Amit Verma, Daniel T. Starczynowski

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)640-650
Number of pages11
JournalNature Cell Biology
Volume21
Issue number5
DOIs
StatePublished - May 1 2019

ASJC Scopus subject areas

  • Cell Biology

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    Smith, M. A., Choudhary, G. S., Pellagatti, A., Choi, K., Bolanos, L. C., Bhagat, T. D., Gordon-Mitchell, S., Von Ahrens, D., Pradhan, K., Steeples, V., Kim, S., Steidl, U., Walter, M., Fraser, I. D. C., Kulkarni, A., Salomonis, N., Komurov, K., Boultwood, J., Verma, A., & Starczynowski, D. T. (2019). U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies. Nature Cell Biology, 21(5), 640-650. https://doi.org/10.1038/s41556-019-0314-5