title: Oncogenically active MYD88 mutations in human lymphoma.
abstract: The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) remains the least curable form of this malignancy despite recent advances in therapy. Constitutive nuclear factor (NF)-κB and JAK kinase signalling promotes malignant cell survival in these lymphomas, but the genetic basis for this signalling is incompletely understood. Here we describe the dependence of ABC DLBCLs on MYD88, an adaptor protein that mediates toll and interleukin (IL)-1 receptor signalling, and the discovery of highly recurrent oncogenic mutations affecting MYD88 in ABC DLBCL tumours. RNA interference screening revealed that MYD88 and the associated kinases IRAK1 and IRAK4 are essential for ABC DLBCL survival. High-throughput RNA resequencing uncovered MYD88 mutations in ABC DLBCL lines. Notably, 29% of ABC DLBCL tumours harboured the same amino acid substitution, L265P, in the MYD88 Toll/IL-1 receptor (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 mucosa-associated lymphoid tissue lymphomas. At a lower frequency, additional mutations were observed in the MYD88 TIR domain, occurring in both the ABC and germinal centre B-cell-like (GCB) DLBCL subtypes. Survival of ABC DLBCL cells bearing the L265P mutation was sustained by the mutant but not the wild-type MYD88 isoform, demonstrating that L265P is a gain-of-function driver mutation. The L265P mutant promoted cell survival by spontaneously assembling a protein complex containing IRAK1 and IRAK4, leading to IRAK4 kinase activity, IRAK1 phosphorylation, NF-κB signalling, JAK kinase activation of STAT3, and secretion of IL-6, IL-10 and interferon-β. Hence, the MYD88 signalling pathway is integral to the pathogenesis of ABC DLBCL, supporting the development of inhibitors of IRAK4 kinase and other components of this pathway for the treatment of tumours bearing oncogenic MYD88 mutations.
authors.affiliation: Metabolism Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Vu N
authors.initials: VN
authors.lastname: Ngo
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Young
authors.forename: Roland
authors.initials: R
authors.lastname: Schmitz
authors.forename: Sameer
authors.initials: S
authors.lastname: Jhavar
authors.forename: Wenming
authors.initials: W
authors.lastname: Xiao
authors.forename: Kian-Huat
authors.initials: KH
authors.lastname: Lim
authors.forename: Holger
authors.initials: H
authors.lastname: Kohlhammer
authors.forename: Weihong
authors.initials: W
authors.lastname: Xu
authors.forename: Yandan
authors.initials: Y
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Shaffer
authors.forename: Paul
authors.initials: P
authors.lastname: Romesser
authors.forename: George
authors.initials: G
authors.lastname: Wright
authors.forename: John
authors.initials: J
authors.lastname: Powell
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: Hans Konrad
authors.initials: HK
authors.lastname: Muller-Hermelink
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Connors
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Rimsza
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Jaffe
authors.forename: Jan
authors.initials: J
authors.lastname: Delabie
authors.forename: Erlend B
authors.initials: EB
authors.lastname: Smeland
authors.forename: Richard I
authors.initials: RI
authors.lastname: Fisher
authors.forename: Rita M
authors.initials: RM
authors.lastname: Braziel
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Tubbs
authors.forename: J R
authors.initials: JR
authors.lastname: Cook
authors.forename: Denny D
authors.initials: DD
authors.lastname: Weisenburger
authors.forename: Wing C
authors.initials: WC
authors.lastname: Chan
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002051:Burkitt Lymphoma / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D053592:Interleukin-1 Receptor-Associated Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D053594:Myeloid Differentiation Factor 88 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009857:Oncogenes / Q000235:genetics*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D016207:Cytokines; C507779:MYD88 protein, human; D050505:Mutant Proteins; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051193:Toll-Like Receptors; D053612:Janus Kinases; C507768:IRAK1 protein, human; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases