Oncogenically active MYD88 mutations in human lymphoma

Vu N. Ngo, Ryan M. Young, Roland Schmitz, Sameer Jhavar, Wenming Xiao, Kian Huat Lim, Holger Kohlhammer, Weihong Xu, Yandan Yang, Hong Zhao, Arthur L. Shaffer, Paul Romesser, George Wright, John Powell, Andreas Rosenwald, Hans Konrad Muller-Hermelink, German Ott, Randy D. Gascoyne, Joseph M. Connors, Lisa M. RimszaElias Campo, Elaine S. Jaffe, Jan Delabie, Erlend B. Smeland, Richard I. Fisher, Rita Braziel, Raymond R. Tubbs, J. R. Cook, Denny D. Weisenburger, Wing C. Chan, Louis M. Staudt

Research output: Contribution to journalArticle

815 Citations (Scopus)

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)-°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, 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 Burkittĝ€ ™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-°B signalling, JAK kinase activation of STAT3, and secretion of IL-6, IL-10 and interferon-2. 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.

Original languageEnglish (US)
Pages (from-to)115-121
Number of pages7
JournalNature
Volume470
Issue number7332
DOIs
StatePublished - Feb 3 2011

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Lymphoma
B-Lymphocytes
Lymphoma, Large B-Cell, Diffuse
Mutation
Interleukin-1 Receptors
Janus Kinases
Cell Survival
Phosphotransferases
Neoplasms
Marginal Zone B-Cell Lymphoma
Germinal Center
Burkitt Lymphoma
Amino Acid Substitution
RNA Interference
Interleukin-10
Interferons
Interleukin-6
Protein Isoforms
Proteins
Phosphorylation

ASJC Scopus subject areas

  • General

Cite this

Ngo, V. N., Young, R. M., Schmitz, R., Jhavar, S., Xiao, W., Lim, K. H., ... Staudt, L. M. (2011). Oncogenically active MYD88 mutations in human lymphoma. Nature, 470(7332), 115-121. https://doi.org/10.1038/nature09671

Oncogenically active MYD88 mutations in human lymphoma. / Ngo, Vu N.; Young, Ryan M.; Schmitz, Roland; Jhavar, Sameer; Xiao, Wenming; Lim, Kian Huat; Kohlhammer, Holger; Xu, Weihong; Yang, Yandan; Zhao, Hong; Shaffer, Arthur L.; Romesser, Paul; Wright, George; Powell, John; Rosenwald, Andreas; Muller-Hermelink, Hans Konrad; Ott, German; Gascoyne, Randy D.; Connors, Joseph M.; Rimsza, Lisa M.; Campo, Elias; Jaffe, Elaine S.; Delabie, Jan; Smeland, Erlend B.; Fisher, Richard I.; Braziel, Rita; Tubbs, Raymond R.; Cook, J. R.; Weisenburger, Denny D.; Chan, Wing C.; Staudt, Louis M.

In: Nature, Vol. 470, No. 7332, 03.02.2011, p. 115-121.

Research output: Contribution to journalArticle

Ngo, VN, Young, RM, Schmitz, R, Jhavar, S, Xiao, W, Lim, KH, Kohlhammer, H, Xu, W, Yang, Y, Zhao, H, Shaffer, AL, Romesser, P, Wright, G, Powell, J, Rosenwald, A, Muller-Hermelink, HK, Ott, G, Gascoyne, RD, Connors, JM, Rimsza, LM, Campo, E, Jaffe, ES, Delabie, J, Smeland, EB, Fisher, RI, Braziel, R, Tubbs, RR, Cook, JR, Weisenburger, DD, Chan, WC & Staudt, LM 2011, 'Oncogenically active MYD88 mutations in human lymphoma', Nature, vol. 470, no. 7332, pp. 115-121. https://doi.org/10.1038/nature09671
Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH et al. Oncogenically active MYD88 mutations in human lymphoma. Nature. 2011 Feb 3;470(7332):115-121. https://doi.org/10.1038/nature09671
Ngo, Vu N. ; Young, Ryan M. ; Schmitz, Roland ; Jhavar, Sameer ; Xiao, Wenming ; Lim, Kian Huat ; Kohlhammer, Holger ; Xu, Weihong ; Yang, Yandan ; Zhao, Hong ; Shaffer, Arthur L. ; Romesser, Paul ; Wright, George ; Powell, John ; Rosenwald, Andreas ; Muller-Hermelink, Hans Konrad ; Ott, German ; Gascoyne, Randy D. ; Connors, Joseph M. ; Rimsza, Lisa M. ; Campo, Elias ; Jaffe, Elaine S. ; Delabie, Jan ; Smeland, Erlend B. ; Fisher, Richard I. ; Braziel, Rita ; Tubbs, Raymond R. ; Cook, J. R. ; Weisenburger, Denny D. ; Chan, Wing C. ; Staudt, Louis M. / Oncogenically active MYD88 mutations in human lymphoma. In: Nature. 2011 ; Vol. 470, No. 7332. pp. 115-121.
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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)-°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, 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 Burkittĝ€ ™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-°B signalling, JAK kinase activation of STAT3, and secretion of IL-6, IL-10 and interferon-2. 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.",
author = "Ngo, {Vu N.} and Young, {Ryan M.} and Roland Schmitz and Sameer Jhavar and Wenming Xiao and Lim, {Kian Huat} and Holger Kohlhammer and Weihong Xu and Yandan Yang and Hong Zhao and Shaffer, {Arthur L.} and Paul Romesser and George Wright and John Powell and Andreas Rosenwald and Muller-Hermelink, {Hans Konrad} and German Ott and Gascoyne, {Randy D.} and Connors, {Joseph M.} and Rimsza, {Lisa M.} and Elias Campo and Jaffe, {Elaine S.} and Jan Delabie and Smeland, {Erlend B.} and Fisher, {Richard I.} and Rita Braziel and Tubbs, {Raymond R.} and Cook, {J. R.} and Weisenburger, {Denny D.} and Chan, {Wing C.} and Staudt, {Louis M.}",
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T1 - Oncogenically active MYD88 mutations in human lymphoma

AU - Ngo, Vu N.

AU - Young, Ryan M.

AU - Schmitz, Roland

AU - Jhavar, Sameer

AU - Xiao, Wenming

AU - Lim, Kian Huat

AU - Kohlhammer, Holger

AU - Xu, Weihong

AU - Yang, Yandan

AU - Zhao, Hong

AU - Shaffer, Arthur L.

AU - Romesser, Paul

AU - Wright, George

AU - Powell, John

AU - Rosenwald, Andreas

AU - Muller-Hermelink, Hans Konrad

AU - Ott, German

AU - Gascoyne, Randy D.

AU - Connors, Joseph M.

AU - Rimsza, Lisa M.

AU - Campo, Elias

AU - Jaffe, Elaine S.

AU - Delabie, Jan

AU - Smeland, Erlend B.

AU - Fisher, Richard I.

AU - Braziel, Rita

AU - Tubbs, Raymond R.

AU - Cook, J. R.

AU - Weisenburger, Denny D.

AU - Chan, Wing C.

AU - Staudt, Louis M.

PY - 2011/2/3

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N2 - 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)-°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, 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 Burkittĝ€ ™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-°B signalling, JAK kinase activation of STAT3, and secretion of IL-6, IL-10 and interferon-2. 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.

AB - 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)-°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, 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 Burkittĝ€ ™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-°B signalling, JAK kinase activation of STAT3, and secretion of IL-6, IL-10 and interferon-2. 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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