Activation of TAK1 by MYD88 L265P drives malignant B-cell growth in non-Hodgkin lymphoma

Stephen Maxted Ansell, L. S. Hodge, F. J. Secreto, M. Manske, Esteban D Braggio, T. Price-Troska, S. Ziesmer, Y. Li, S. H. Johnson, Steven Hart, Jean-Pierre Kocher, George Vasmatzis, Asher A Chanan Khan, Morie Gertz, Rafael Fonseca, A. Dogan, James R Cerhan, Anne J Novak

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Massively parallel sequencing analyses have revealed a common mutation within the MYD88 gene (MYD88L265P) occurring at high frequencies in many non-Hodgkin lymphomas (NHLs) including the rare lymphoplasmacytic lymphoma, Waldenström's macroglobulinemia (WM). Using whole-exome sequencing, Sanger sequencing and allele-specific PCR, we validate the initial studies and detect the MYD88L265P mutation in the tumor genome of 97% of WM patients analyzed (n=39). Due to the high frequency of MYD88 mutation in WM and other NHL, and its known effects on malignant B-cell survival, therapeutic targeting of MYD88 signaling pathways may be clinically useful. However, we are lacking a thorough characterization of the role of intermediary signaling proteins on the biology of MYD88L265P-expressing B cells. We report here that MYD88L265P signaling is constitutively active in both WM and diffuse large B-cell lymphoma cells leading to heightened MYD88L265P, IRAK and TRAF6 oligomerization and NF-kB activation. Furthermore, we have identified the signaling protein, TAK1, to be an essential mediator of MYD88 L265P-driven signaling, cellular proliferation and cytokine secretion in malignant B cells. Our studies highlight the biological significance of MYD88L265P in NHL and reveal TAK1 inhibition to be a potential therapeutic strategy for the treatment of WM and other diseases characterized by MYD88L265P.

Original languageEnglish (US)
Article number20144
JournalBlood Cancer Journal
Volume4
Issue number2
DOIs
StatePublished - 2014

Fingerprint

Waldenstrom Macroglobulinemia
Non-Hodgkin's Lymphoma
B-Lymphocytes
Growth
TNF Receptor-Associated Factor 6
Exome
High-Throughput Nucleotide Sequencing
Mutation
Lymphoma, Large B-Cell, Diffuse
NF-kappa B
Mutation Rate
Lymphoma
Cell Survival
Proteins
Therapeutics
Alleles
Cell Proliferation
Genome
Cytokines
Polymerase Chain Reaction

Keywords

  • lymphoma
  • MYD88
  • TAK1
  • Waldenstrom

ASJC Scopus subject areas

  • Oncology
  • Hematology

Cite this

Activation of TAK1 by MYD88 L265P drives malignant B-cell growth in non-Hodgkin lymphoma. / Ansell, Stephen Maxted; Hodge, L. S.; Secreto, F. J.; Manske, M.; Braggio, Esteban D; Price-Troska, T.; Ziesmer, S.; Li, Y.; Johnson, S. H.; Hart, Steven; Kocher, Jean-Pierre; Vasmatzis, George; Chanan Khan, Asher A; Gertz, Morie; Fonseca, Rafael; Dogan, A.; Cerhan, James R; Novak, Anne J.

In: Blood Cancer Journal, Vol. 4, No. 2, 20144, 2014.

Research output: Contribution to journalArticle

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abstract = "Massively parallel sequencing analyses have revealed a common mutation within the MYD88 gene (MYD88L265P) occurring at high frequencies in many non-Hodgkin lymphomas (NHLs) including the rare lymphoplasmacytic lymphoma, Waldenstr{\"o}m's macroglobulinemia (WM). Using whole-exome sequencing, Sanger sequencing and allele-specific PCR, we validate the initial studies and detect the MYD88L265P mutation in the tumor genome of 97{\%} of WM patients analyzed (n=39). Due to the high frequency of MYD88 mutation in WM and other NHL, and its known effects on malignant B-cell survival, therapeutic targeting of MYD88 signaling pathways may be clinically useful. However, we are lacking a thorough characterization of the role of intermediary signaling proteins on the biology of MYD88L265P-expressing B cells. We report here that MYD88L265P signaling is constitutively active in both WM and diffuse large B-cell lymphoma cells leading to heightened MYD88L265P, IRAK and TRAF6 oligomerization and NF-kB activation. Furthermore, we have identified the signaling protein, TAK1, to be an essential mediator of MYD88 L265P-driven signaling, cellular proliferation and cytokine secretion in malignant B cells. Our studies highlight the biological significance of MYD88L265P in NHL and reveal TAK1 inhibition to be a potential therapeutic strategy for the treatment of WM and other diseases characterized by MYD88L265P.",
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AU - Manske, M.

AU - Braggio, Esteban D

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AU - Johnson, S. H.

AU - Hart, Steven

AU - Kocher, Jean-Pierre

AU - Vasmatzis, George

AU - Chanan Khan, Asher A

AU - Gertz, Morie

AU - Fonseca, Rafael

AU - Dogan, A.

AU - Cerhan, James R

AU - Novak, Anne J

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