Somatic MyD88 mutations and a germline IRAK2 variant contribute to lymphoma by differential effects on NF-κB (INM7P.354)

Abstract Within innate immune signaling pathways, Myeloid differentiation (MyD) 88 and Interleukin-1 receptor associated kinases (IRAKs) fulfill pivotal roles downstream of multiple Toll-like receptors (TLR). Somatic MyD88 mutations in B cells were reported to affect lymphomagenesis by constitutive hyperactivation of NF-κB. We here show that oncogenic mutants augment spontaneous TIR domain oligomerization into so-called Myddosome signaling complexes driving NF-κB activation. Blocking of MyD88 oligomerization consequently induced the death of MyD88-mutated but not unmutated lymphoma cells. In line with the involvement of the MyD88 axis in lymphomagenesis we detected a genetic association of a coding germline variant of IRAK2, a MyD88 interactor, with increased risk (OR = 1.43, 95% confidence interval 1.06-1.93, p=0.018) to develop lymphoma in a German cohort (n=387). This variant is frequently found in 15-44% of individuals of different ethnic groups. Unexpectedly, this variant was associated with reduced NF-κB activation and cytokine responses to TLR agonists in healthy donors. Mechanistically, the IRAK2 variant retained intact binding to but impaired ubiquitination of TRAF6, a vital step in signal transduction. Thus our findings confirm the involvement of MyD88/IRAK in lymphoma but suggest that MyD88 and IRAK2 may contribute differently to oncogenic signaling. Additionally we highlight IRAK2 genetic variants as a critical factor and potentially novel biomarker for human lymphomagenesis.