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

S. M. Ansell, L. S. Hodge, F. J. Secreto, M. Manske, E. Braggio, T. Price-Troska, S. Ziesmer, Y. Li, S. H. Johnson, S. N. Hart, J. P.A. Kocher, G. Vasmatzis, A. Chanan-Kahn, M. Gertz, R. Fonseca, A. Dogan, J. R. Cerhan, A. J. Novak

Research output: Contribution to journalArticle

50 Scopus citations

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 - Feb 2014

Keywords

  • MYD88
  • TAK1
  • Waldenstrom
  • lymphoma

ASJC Scopus subject areas

  • Hematology
  • Oncology

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