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

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.

Activation of lymphoma-associated MyD88 mutations via allostery-induced TIR-domain oligomerization

“…Whereas others have noted the hyperactive effect of oncogenic-mutations and their effect on IRAK and TAK1 kinases, 3,36 the underlying cause of these observations has remained elusive. Our data now provide a molecular explanation of this phenomenon.…”

“…Recent analyses of the receptor TIR domains proposed residues of the central b strands form highly stable "hubs" within an evolutionarily conserved intradomain communication network, acting to relay protein-protein interactions from one end of the structure to the other. 36 Thus, RMSF minima map to 5 communication hubs, H1 to H5. 35 Strikingly, several lymphoma-associated mutations map exactly to the H3 (M232) or H4 (L265) positions, and, with the exception of S243N and T294P, all the remaining oncogenic mutations map to the interaction plane spanned by residues corresponding to RMSF minima (V217F, S219C, I220T, and S222R; Figure 4E), suggesting that lymphoma-associated mutations in fact modulate force transduction during oligomerization.…”

Role of MYD88 in lymphoplasmacytic lymphoma diagnosis and pathogenesis

“…11,26,27 Overall, these data, along with pivotal evidences from phase I studies, 31 support the clinical investigation of the BTK inhibitor ibrutinib as targeted treatment of LPL/WM.…”

“…Consistently, in B-cell tumors, mutant MYD88 results in uncontrolled formation of the MYD88/IRAK complex, which translates into the recruitment of TRAF6, constitutive phosphorylation of TAK1, and, ultimately, the elevation of NF-B activity. 11,23,26 In LPL, mutant MYD88 promotes NF-B also by binding and activating the Bruton's tyrosine kinase (BTK) (Figure 1). 27 Based on these observations, a model can be envisaged in which MYD88 mutations trigger NF-B via dual but independent pathways, namely signaling through IRAK1-4 and signaling through BTK.…”

“…27 In ABC-DLBCL and LPL/WM, MYD88 mutations also result into the deregulation of JAK-STAT3 as an additional important downstream effects. 23,26 At the cellular level, the signaling promoted by MYD88 mutations sustains tumor cell survival in both LPL/WM and ABC-DLBCL, documenting that they are gain-of-function driver events in these lymphoma types. 11,22,27 When introduced into normal mature B cells, the MYD88 L265P mutation is sufficient to trigger NF-B signaling and rapid cell proliferation.…”