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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.

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Division of Hematology, Mayo Clinic, Rochester, MN, USA.
Division of Hematology, Mayo Clinic, Scottsdale, AZ, USA.
Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
Division of Hematology, Mayo Clinic, Jacksonville, FL, USA.
Division of Anatomic Pathology and Hematopathology, Mayo Clinic, Rochester, MN, USA.
Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.


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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