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.
Highlights
Somatic mutations in genes whose protein products are involved in cell signaling pathways, apoptosis or inflammatory responses contribute to both the pathogenesis and progression of nonHodgkin lymphoma (NHL).[1,2,3,4,5,6,7]
MYD88L265P was detected at a higher incidence, 30%, in patients with activated B cell-like diffuse large B-cell lymphoma (DLBCL) and at lower levels in patients with primary central nervous system lymphoma, marginal zone lymphoma (MZL), Burkitt’s lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma and chronic lymphocytic leukemia.[8,10,11]
The reported prevalence of MYD88L265P appears to be highest in patients diagnosed with Waldenstrom’s macroglobulinemia (WM)
Summary
Somatic mutations in genes whose protein products are involved in cell signaling pathways, apoptosis or inflammatory responses contribute to both the pathogenesis and progression of nonHodgkin lymphoma (NHL).[1,2,3,4,5,6,7] Recent analyses of generation sequencing data have revealed common mutations in the myeloid differentiation factor gene, MYD88, in malignant B cells from patients with NHL.[1,8,9] While other mutations in MYD88 have been reported, by far the most highly conserved variant involves a single base-pair substitution translating into an amino-acid switch from leucine to proline at position 265 (MYD88L265P).[10].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
