title: A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia.
abstract: Myeloid differentiation factor 88 (MYD88) L265P somatic mutation is highly prevalent in Waldenström macroglobulinemia (WM) and supports malignant growth through nuclear factor κB (NF-κB). The signaling cascade(s) by which MYD88 L265P promotes NF-κB activation in WM remain unclear. By lentiviral knockdown or use of a MYD88 inhibitor, decreased phosphorylation of the NF-κB gatekeeper IκBα and survival occurred in MYD88 L265P-expressing WM cells. Conversely, WM cells engineered to overexpress MYD88 L265P showed enhanced survival. Coimmunoprecipitation studies identified Bruton tyrosine kinase (BTK) complexed to MYD88 in L265P-expressing WM cells, with preferential binding of MYD88 to phosphorylated BTK (pBTK). Increased pBTK was also observed in WM cells transduced to overexpress L265P vs wild-type MYD88. Importantly, MYD88 binding to BTK was abrogated following treatment of MYD88 L265P-expressing cells with a BTK kinase inhibitor. Inhibition of BTK or interleukin-1 receptor-associated kinase 1 and 4 (IRAK-1 and -4) kinase activity induced apoptosis of WM cells, and their combination resulted in more robust inhibition of NF-κB signaling and synergistic WM cell killing. The results establish BTK as a downstream target of MYD88 L265P signaling, and provide a framework for the study of BTK inhibitors alone, and in combination with IRAK inhibitors for the treatment of WM.
authors.affiliation: Bing Center for Waldenstrom's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Yangsheng
authors.initials: Y
authors.lastname: Zhou
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.forename: Lian
authors.initials: L
authors.lastname: Xu
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Manning
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Patterson
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Buhrlage
authors.forename: Nathanael
authors.initials: N
authors.lastname: Gray
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Hunter
authors.forename: Steven P
authors.initials: SP
authors.lastname: Treon
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D017209:Apoptosis; D015153:Blotting, Western; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D008156:Luciferases / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D008258:Waldenstrom Macroglobulinemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D034741:RNA, Small Interfering; D008156:Luciferases; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases