TY - JOUR
T1 - U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies
AU - Smith, Molly A.
AU - Choudhary, Gaurav S.
AU - Pellagatti, Andrea
AU - Choi, Kwangmin
AU - Bolanos, Lyndsey C.
AU - Bhagat, Tushar D.
AU - Gordon-Mitchell, Shanisha
AU - Von Ahrens, Dagny
AU - Pradhan, Kith
AU - Steeples, Violetta
AU - Kim, Sanghyun
AU - Steidl, Ulrich
AU - Walter, Matthew
AU - Fraser, Iain D.C.
AU - Kulkarni, Aishwarya
AU - Salomonis, Nathan
AU - Komurov, Kakajan
AU - Boultwood, Jacqueline
AU - Verma, Amit
AU - Starczynowski, Daniel T.
N1 - Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/5/1
Y1 - 2019/5/1
N2 - 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.
AB - 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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U2 - 10.1038/s41556-019-0314-5
DO - 10.1038/s41556-019-0314-5
M3 - Article
C2 - 31011167
AN - SCOPUS:85064756006
SN - 1465-7392
VL - 21
SP - 640
EP - 650
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 5
ER -