Oncogenically active MYD88 mutations in human lymphoma

被引:1166
作者
Ngo, Vu N. [1 ]
Young, Ryan M. [1 ]
Schmitz, Roland [1 ]
Jhavar, Sameer [1 ]
Xiao, Wenming [2 ]
Lim, Kian-Huat [1 ]
Kohlhammer, Holger [1 ]
Xu, Weihong [1 ]
Yang, Yandan [1 ]
Zhao, Hong [1 ]
Shaffer, Arthur L. [1 ]
Romesser, Paul [1 ,3 ]
Wright, George [4 ]
Powell, John [2 ]
Rosenwald, Andreas [5 ]
Muller-Hermelink, Hans Konrad [5 ]
Ott, German [6 ,7 ]
Gascoyne, Randy D. [8 ]
Connors, Joseph M. [8 ]
Rimsza, Lisa M. [9 ,10 ]
Campo, Elias [11 ]
Jaffe, Elaine S. [12 ]
Delabie, Jan [13 ]
Smeland, Erlend B. [14 ,15 ]
Fisher, Richard I. [10 ,16 ]
Braziel, Rita M. [10 ,17 ]
Tubbs, Raymond R. [10 ,18 ]
Cook, J. R. [10 ,18 ]
Weisenburger, Denny D. [19 ,20 ]
Chan, Wing C. [19 ,20 ]
Staudt, Louis M. [1 ]
机构
[1] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA
[2] NIH, Bioinformat & Mol Anal Sect, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA
[3] NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA
[4] NCI, Biometr Res Branch, DCTD, NIH, Bethesda, MD 20892 USA
[5] Univ Wurzburg, Dept Pathol, D-97080 Wurzburg, Germany
[6] Robert Bosch Krankenhaus, Dept Clin Pathol, D-70376 Stuttgart, Germany
[7] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70376 Stuttgart, Germany
[8] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada
[9] Univ Arizona, Dept Pathol, Tucson, AZ 85724 USA
[10] SW Oncol Grp, Ann Arbor, MI 48106 USA
[11] Univ Barcelona, Hosp Clin, E-08036 Barcelona, Spain
[12] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA
[13] Univ Hosp, Rikshosp, Pathol Clin, N-0310 Oslo, Norway
[14] Univ Hosp, Rikshosp, Inst Canc Res, N-0310 Oslo, Norway
[15] Univ Oslo, Norwegian Radium Hosp, Fac Div, Ctr Canc Biomed, N-0310 Oslo, Norway
[16] Univ Rochester, Sch Med, James P Wilmot Canc Ctr, Rochester, NY 14642 USA
[17] Oregon Hlth & Sci Univ, Portland, OR 97239 USA
[18] Cleveland Clin, Pathol & Lab Med Inst, Cleveland, OH 44195 USA
[19] Univ Nebraska Med Ctr, Dept Pathol, Omaha, NE 68198 USA
[20] Univ Nebraska Med Ctr, Dept Microbiol, Omaha, NE 68198 USA
关键词
B-CELL LYMPHOMA; NF-KAPPA-B; TNFAIP3; A20; GENE; INHIBITORS; SIGNATURES; PATHWAYS; SURVIVAL; SUBTYPES; KINASE;
D O I
10.1038/nature09671
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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(1). Constitutive nuclear factor (NF)-kappa B 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(2,3), 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-kappa B signalling, JAK kinase activation of STAT3, and secretion of IL-6, IL-10 and interferon-beta. 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.
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页码:115 / U133
页数:7
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