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Blood Cancer J. 2014 Feb 14;4:e183. doi: 10.1038/bcj.2014.4.

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

Author information

1
Division of Hematology, Mayo Clinic, Rochester, MN, USA.
2
Division of Hematology, Mayo Clinic, Scottsdale, AZ, USA.
3
Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
4
Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
5
Division of Hematology, Mayo Clinic, Jacksonville, FL, USA.
6
Division of Anatomic Pathology and Hematopathology, Mayo Clinic, Rochester, MN, USA.
7
Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.

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-κB activation. Furthermore, we have identified the signaling protein, TAK1, to be an essential mediator of MYD88L265P-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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