A new era for Waldenstrom macroglobulinemia: MYD88 L265P.

摘要

The discovery of a mutation in MYD88 is significant given its role as an adaptor molecule in Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling. Following TLR or IL-1R stimulation, MYD88 is recruited to the activated receptor complex as a homodimer, which complexes with IL-lR-associated kinase (IRAK) 4 to activate IRAKI. Tumor necrosis factor receptor—associated factor 6 is then activated leading to nuclear factor kB (NF-kB) activation via IkBo: phosphorylation. Similar to the findings by Ngo et al9 in MYD88 L265P-expressing activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) cell lines, inhibition of MYD88/ IRAK signaling attenuates NF-kB signaling and survival of MYD88 L265P-expressing WM cells.1'2'8'10 Correspondingly, WM cell survival is enhanced by MYD88 L265P overexpression. Additionally, Yang et al10 have shown that inhibition of MYD88 in L265P-expressing WM cells is accompanied by decreased activation of Bruton tyrosine kinase (BTK), whereas overexpression of MYD88 L265P enhances BTK phosphorylation. These studies also show that IRAK and BTK independently direct downstream NF-kB activation and combined use of IRAK and BTK inhibitors leads to synergistic tumor cell killing in MYD88 L265P-expressing WM cells. These studies would suggest a model wherein MYD88 L265P triggers NF-kB via dual, but independent pathways, which signal through BTK and/or IRAKI/IRAK4.