U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.
Molly A SmithGaurav S ChoudharyAndrea PellagattiKwangmin ChoiLyndsey C BolanosTushar D BhagatShanisha Gordon-MitchellDagny Von AhrensKith PradhanVioletta SteeplesSanghyun KimUlrich SteidlMatthew WalterIain D C FraserAishwarya KulkarniNathan SalomonisKakajan KomurovJacqueline BoultwoodAmit K VermaDaniel T StarczynowskiPublished in: Nature cell biology (2019)
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.
Keyphrases
- acute myeloid leukemia
- nuclear factor
- innate immune
- poor prognosis
- binding protein
- allogeneic hematopoietic stem cell transplantation
- transcription factor
- atrial fibrillation
- toll like receptor
- genome wide
- oxidative stress
- signaling pathway
- drug induced
- cell death
- acute lymphoblastic leukemia
- cell cycle arrest
- intensive care unit
- dna methylation
- blood pressure
- inflammatory response
- pi k akt
- hepatitis b virus
- long non coding rna
- copy number
- peripheral blood
- body composition
- protein protein
- high intensity
- mechanical ventilation
- genome wide identification