Editors' ChoiceImmunology

Cancer and the death domain

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Science Signaling  04 Jun 2019:
Vol. 12, Issue 584, eaay2357
DOI: 10.1126/scisignal.aay2357

Inclusion of a death domain in an alternatively spliced isoform of the kinase IRAK4 increases leukemic burden.

Mutations in RNA-splicing factor genes occur in about 50% of patients with myelodysplastic syndromes (MDS), which may progress to acute myeloid leukemia (AML). Smith et al. analyzed exon inclusion and exclusion events and found that inclusion of exon 4 in the mRNA encoding the kinase IRAK4 correlated with worse prognosis in both MDS and AML patients. Interaction of IRAK4 with the scaffold protein MyD88 in response to TLR signaling results in the activation of the proinflammatory transcription factor nuclear factor κB (NF-κB). The longer IRAK4 isoform (IRAK4-L) had an N-terminal death domain that was not present in the shorter isoform (IRAK4-S). In HEK cells, expression of IRAK4-L increased NF-κB activation to a greater extent than did expression of IRAK4-S. In AML cell lines, MyD88 coimmunoprecipitated with IRAK4-L but not IRAK4-S. THP1 cells with knockdown of IRAK4-L formed fewer colonies (an indicator of reduced progenitor function), and, when xenografted into mice, resulted in a lower leukemic burden. This effect was reproduced by treating mice xenografted with THP1 cells expressing both IRAK4 isoforms with an IRAK4 inhibitor. Inclusion of exon 4 in IRAK4 correlated with mutations in the gene encoding the RNA splicing factor U2AF1. Expression of U2AF1 with an S34F mutation increased the expression of a reporter designed to measure IRAK4 exon 4 splicing in HEK cells and enhanced NF-κB activation in K562 cells. Pharmacological inhibition of IRAK4 decreased the survival and colony formation ability of MDS or AML patient cells expressing the U2AF1 S34F mutant and reduced engraftment in mice xenografted with mutant-expressing MDS patient cells. Thus, the addition of a death domain to IRAK4 resulting from an exon inclusion event mediated by mutant U2AF1 increases MyD88-dependent activation of NF-κB and leukemic burden.

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