SYK is activated by mutated MYD88 and drives pro-survival signaling in MYD88 driven B-cell lymphomas Journal Article

   


Authors: Munshi, M.; Liu, X.; Chen, J. G.; Xu, L.; Tsakmaklis, N.; Demos, M. G.; Kofides, A.; Guerrera, M. L.; Jimenez, C.; Chan, G. G.; Hunter, Z. R.; Palomba, M. L.; Argyropoulos, K. V.; Meid, K.; Keezer, A.; Gustine, J.; Dubeau, T.; Castillo, J. J.; Patterson, C. J.; Wang, J.; Buhrlage, S. J.; Gray, N. S.; Treon, S. P.; Yang, G.
Article Title: SYK is activated by mutated MYD88 and drives pro-survival signaling in MYD88 driven B-cell lymphomas
Abstract: Activating MYD88 mutations promote pro-survival signaling through BTK and HCK, both targets of ibrutinib. Despite high response rates, complete responses to ibrutinib are lacking, and other MYD88 triggered pro-survival pathways may contribute to primary drug resistance. B-cell receptor (BCR) signaling has been observed in lymphomas driven by mutated MYD88, even without activating the BCR pathway mutations. We identified activated SYK (p-SYK), a component of BCR in complex with MYD88 in MYD88-mutated WM and ABC DLBCL lymphoma cells. Confocal microscopy confirmed co-localization of MYD88 with SYK in MYD88-mutated cells. Knockdown of MYD88 or use of a MYD88 signaling inhibitor abrogated SYK activation, while expression of mutated but not wild-type MYD88 amplified p-SYK in MYD88-mutated and wild-type lymphoma cells. Knockdown of SYK or use of inhibitors targeting SYK blocked p-STAT3 and p-AKT signaling in MYD88-mutated cells. Cell viability analysis showed that combining ibrutinib and SYK inhibitors triggered synthetic killing of MYD88-mutated lymphoma cells. Our findings extend the spectrum of mutated MYD88 pro-survival signaling to include SYK directed BCR cross talk in MYD88-mutated lymphomas. Targeting SYK in combination with ibrutinib produces synthetic lethality, providing a framework for the clinical investigation of ibrutinib with SYK inhibitors in MYD88-mutated lymphomas. © 2020, The Author(s).
Keywords: signal transduction; protein kinase b; controlled study; protein phosphorylation; unclassified drug; gene mutation; human cell; cancer combination chemotherapy; drug potentiation; antineoplastic agent; cell viability; cell survival; stat3 protein; enzyme inhibition; gene amplification; confocal microscopy; protein protein interaction; enzyme activation; enzyme activity; wild type; b cell lymphoma; cellular distribution; myeloid differentiation factor 88; cancer cell destruction; lethality; receptor cross-talk; b lymphocyte receptor; akt signaling; protein kinase syk; synergistic effect; bruton tyrosine kinase; ibrutinib; gene knockdown; human; article; tmd8 cell line; entospletinib; protein kinase syk inhibitor; tamatinib; bcwm.1 cell line; hbl-1 [human diffuse large b-cell lymphoma] cell line; mwcl-1 cell line; oci-ly19 cell line; oci-ly3 cell line; oci-ly7 cell line; ramos cell line; waldenstrom macroglobulinemia cell line
Journal Title: Blood Cancer Journal
Volume: 10
ISSN: 2044-5385
Publisher: Nature Publishing Group  
Date Published: 2020-01-31
Start Page: 12
Language: English
DOI: 10.1038/s41408-020-0277-6
PUBMED: 32005797
PROVIDER: scopus
PMCID: PMC6994488
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85078825765&doi=10.1038%2fs41408-020-0277-6&partnerID=40&md5=b7322bfe7af536f44ae89f11f379c766
Notes: Article -- Export Date: 2 March 2020 -- Source: Scopus
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MSK Authors
  1. Maria Lia Palomba
    415 Palomba
  2. Kimon Argyropoulos
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