Splicing the innate immune signalling in leukaemia

Abstract

Components of the spliceosome are frequently mutated in haematopoietic malignancies. Identification of mis-spliced genes promoting transformation will uncover novel targeted therapies. Now, a long isoform of IRAK4 is shown to be upregulated in a subset of acute myeloid leukaemia patients, conferring susceptibility for IRAK4 inhibition therapy.

Fig. 1 |. Differential splicing of IRAK4 leads to a specific long isoform that can be therapeutically targeted.

a, Normal CD34⁺ stem and progenitor cells preferentially express a short isoform of IRAK4 (IRAK4-S), which promotes stronger activation of MAPK signalling than the NF-κB pathway. b, Mutations in U2AF1 lead to predominant expression of a long isoform of IRAK4 (IRAK4-L). The N-terminal domain retained in IRAK4-L interacts with the death domain of MYD88, facilitating the assembly of the myddosome complex, which mediates IRAK4 autotransphosphorylation and NF-κB maximal activation. Treatment with IRAK4 inhibitors decreases NF-κB signalling and promotes the differentiation of AML cells in vitro, significantly reducing the tumour burden in in vivo experiments. Ex, exon.