Oncogenically active MYD88 mutations in human lymphoma
| Autor: | Erlend B. Smeland, Elaine S. Jaffe, Richard I. Fisher, Randy D. Gascoyne, Kian-Huat Lim, Sameer Jhavar, Vu N. Ngo, George E. Wright, Louis M. Staudt, Roland Schmitz, Elias Campo, Holger Kohlhammer, Hans K. Müller-Hermelink, German Ott, Paul B. Romesser, Arthur L. Shaffer, Ryan M. Young, Lisa M. Rimsza, Yandan Yang, Denny D. Weisenburger, John Powell, James R. Cook, Jan Delabie, Wenming Xiao, Wing C. Chan, Joseph M. Connors, Weihong Xu, Raymond R. Tubbs, Andreas Rosenwald, Rita M. Braziel, Hong Zhao |
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| Rok vydání: | 2010 |
| Předmět: |
STAT3 Transcription Factor
Cell Survival Molecular Sequence Data Biology medicine.disease_cause Article immune system diseases Cell Line Tumor hemic and lymphatic diseases medicine Humans Amino Acid Sequence Phosphorylation Kinase activity Janus Kinases Mutation Multidisciplinary Sequence Analysis RNA Kinase Toll-Like Receptors NF-kappa B High-Throughput Nucleotide Sequencing Receptors Interleukin-1 Lymphoma B-Cell Marginal Zone Oncogenes IRAK4 medicine.disease Burkitt Lymphoma Protein Structure Tertiary Lymphoma Interleukin-1 Receptor-Associated Kinases Amino Acid Substitution Myeloid Differentiation Factor 88 Cancer research Cytokines Mutant Proteins RNA Interference Lymphoma Large B-Cell Diffuse Carcinogenesis Janus kinase Hydrophobic and Hydrophilic Interactions Diffuse large B-cell lymphoma Signal Transduction |
| Zdroj: | Nature. 470:115-119 |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/nature09671 |
| Popis: | 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 therapy1. 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 signalling2,3, 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, theMYD88 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. |
| Databáze: | OpenAIRE |
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