Highly Recurrent MYD88 Mutations That Promote Human Lymphoma Cell Survival

The ABC subtype of diffuse large B cell lymphoma (DLBCL) remains the least curable form of this lymphoma despite recent advances in therapy. We have combined structural and functional genomics to triangulate on new oncogenic mechanisms and devise new therapeutic strategies. RNA interference screening revealed a dependence of ABC DLBCL cell lines on MYD88 and IRAK1. High throughput resequencing of RNA (RNA-Seq) revealed frequent somatic mutations in MYD88 that preferentially occurred in the ABC DLBCL subtype. Remarkably, 28% of ABC DLBCLs harbored the same amino acid substitution, L265P, in the MYD88 TIR domain at an evolutionarily invariant residue in its hydrophobic core. This mutation was rare or absent in other DLBCL subtypes and Burkitt''s lymphoma, but was observed in 9% of MALT lymphomas. At a lower frequency, multiple other mutations were observed in the MYD88 TIR domain, occurring in both the ABC and GCB subtypes of DLBCL. Survival of ABC DLBCL cells bearing the L265P mutation was sustained by the mutant but not wild type MYD88 isoform, demonstrating that this MYD88 mutant is oncogenic and gain-of-function. The L265P mutant promoted cell survival by spontaneously assembling a protein complex that triggered the phosphorylation of IRAK1, leading to NF-kB signaling, JAK kinase activation of STAT3, and secretion of the cytokines IL-6, IL-10 and interferon-beta. These findings demonstrate that the MYD88 signaling pathway is integral to the pathogenesis of ABC DLBCL, providing a genetic rationale for therapeutic targeting of the MYD88 signaling pathway in this lymphoma subtype.