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A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia.
Blood. 2013 Aug 15; 122(7):1222-32.Blood

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+Show Affiliations

Bing Center for Waldenstrom's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA 02215, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23836557

Citation

Yang, Guang, et al. "A Mutation in MYD88 (L265P) Supports the Survival of Lymphoplasmacytic Cells By Activation of Bruton Tyrosine Kinase in Waldenström Macroglobulinemia." Blood, vol. 122, no. 7, 2013, pp. 1222-32.
Yang G, Zhou Y, Liu X, et al. A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia. Blood. 2013;122(7):1222-32.
Yang, G., Zhou, Y., Liu, X., Xu, L., Cao, Y., Manning, R. J., Patterson, C. J., Buhrlage, S. J., Gray, N., Tai, Y. T., Anderson, K. C., Hunter, Z. R., & Treon, S. P. (2013). A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia. Blood, 122(7), 1222-32. https://doi.org/10.1182/blood-2012-12-475111
Yang G, et al. A Mutation in MYD88 (L265P) Supports the Survival of Lymphoplasmacytic Cells By Activation of Bruton Tyrosine Kinase in Waldenström Macroglobulinemia. Blood. 2013 Aug 15;122(7):1222-32. PubMed PMID: 23836557.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia. AU - Yang,Guang, AU - Zhou,Yangsheng, AU - Liu,Xia, AU - Xu,Lian, AU - Cao,Yang, AU - Manning,Robert J, AU - Patterson,Christopher J, AU - Buhrlage,Sara J, AU - Gray,Nathanael, AU - Tai,Yu-Tzu, AU - Anderson,Kenneth C, AU - Hunter,Zachary R, AU - Treon,Steven P, Y1 - 2013/07/08/ PY - 2013/7/10/entrez PY - 2013/7/10/pubmed PY - 2013/11/8/medline SP - 1222 EP - 32 JF - Blood JO - Blood VL - 122 IS - 7 N2 - 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. SN - 1528-0020 UR - https://www.unboundmedicine.com/medline/citation/23836557/A_mutation_in_MYD88__L265P__supports_the_survival_of_lymphoplasmacytic_cells_by_activation_of_Bruton_tyrosine_kinase_in_Waldenström_macroglobulinemia_ L2 - https://ashpublications.org/blood/article-lookup/doi/10.1182/blood-2012-12-475111 DB - PRIME DP - Unbound Medicine ER -