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Nat Cell Biol. 2019 May;21(5):640-650. doi: 10.1038/s41556-019-0314-5. Epub 2019 Apr 22.

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

Author information

1
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
2
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA.
3
Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA.
4
Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford and Oxford BRC Haematology Theme, Oxford, UK.
5
Department of Medicine, Washington University, St. Louis, MO, USA.
6
Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, MD, USA.
7
Department of Electrical Engineering and Computer Science, University of Cincinnati, Cincinnati, OH, USA.
8
Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
9
Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.
10
Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford and Oxford BRC Haematology Theme, Oxford, UK. jacqueline.boultwood@ndcls.ox.ac.uk.
11
Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA. amit.verma@einstein.yu.edu.
12
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Daniel.Starczynowski@cchmc.org.
13
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA. Daniel.Starczynowski@cchmc.org.
14
Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA. Daniel.Starczynowski@cchmc.org.

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.

PMID:
31011167
DOI:
10.1038/s41556-019-0314-5

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