A new role for the SRC family kinase HCK as a driver of SYK activation in MYD88 mutated lymphomas.

Abstract

The SRC family kinase (SFK) HCK is transcriptionally upregulated and activated by mutated MYD88 (MYD88Mut), a key adaptor for Toll-receptor signaling. HCK activates BTK, AKT, and ERK in MYD88Mut lymphomas. SYK, a B-cell receptor (BCR) component, is activated in MYD88Mut lymphoma cells. Although the SFK LYN serves as a trigger for SYK activation in MYD88Mut ABC DLBCL cells, LYN activity is muted in MYD88Mut Waldenstrom macroglobulinemia (WM) cells. We therefore investigated a role for HCK in mediating SYK activation. Overexpression of wild-type (WT) (HCKWT) or gatekeeper mutated (HCKThr333Met) HCK in MYD88Mut lymphoma cells triggered SYK activation. Conversely, HCK knockdown reduced p-SYK in MYD88Mut lymphoma cells. Coimmunoprecipitation experiments showed that HCK was complexed with p-SYK in MYD88Mut BCWM.1 and TMD8 cells, but not in MYD88 WT Ramos cells. Rescue experiments in MYD88Mut lymphoma cells expressing HCKThr333Met led to persistent HCK and SYK activation and resistance to the HCK inhibitor A419259. Treatment of primary MYD88Mut WM cells with A419259 reduced p-HCK and p-SYK expression. Taken together, our findings show that SYK is activated by HCK in MYD88Mut B-cell lymphomas cells, broaden the prosurvival signaling generated by aberrant HCK expression in response to MYD88Mut, and help define HCK as an important therapeutic target in MYD88Mut B-cell lymphomas.

• Authors: Manit Munshi, Xia Liu, Amanda Kofides, Nickolas Tsakmaklis, Maria Luisa Guerrera, Zachary R Hunter, M Lia Palomba, Kimon V Argyropoulos, Christopher J Patterson, Alexa G Canning, Kirsten Meid, Joshua Gustine, Andrew R Branagan, Catherine A Flynn, Shayna Sarosiek, Jorge J Castillo, Jinhua Wang, Sara J Buhrlage, Nathanael S Gray, Nikhil C Munshi, Kenneth C Anderson, Steven P Treon, Guang Yang
• Journal: Blood advances (Blood Adv) Vol. 6 Issue 11 Pg. 3332-3338 (06 14 2022) ISSN: 2473-9537 [Electronic] United States
• PMID: 35255496 (Publication Type: Journal Article)
• Copyright: © 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• MYD88 protein, human
• Myeloid Differentiation Factor 88
• HCK protein, human
• Proto-Oncogene Proteins c-hck
• SYK protein, human
• Syk Kinase
• src-Family Kinases

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Humans
• Lymphoma, B-Cell (enzymology, genetics, metabolism)
• Myeloid Differentiation Factor 88 (genetics, metabolism)
• Proto-Oncogene Proteins c-hck (metabolism)
• Syk Kinase (genetics, metabolism)
• src-Family Kinases (metabolism)