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 BCR component is activated in MYD88Mut lymphoma cells. While the SFK LYN serves as a trigger for SYK activation in MYD88Mut ABC DLBCL cells, LYN activity is muted in MYD88Mut WM cells. We therefore investigated a role for HCK in mediating SYK activation. Over-expression of wild-type (HCKWT) or gatekeeper mutated (HCKThr333Met) HCK in MYD88Mut lymphoma cells triggered SYK activation. Conversely, HCK knockdown reduced p-SYK in MYD88Mut lymphoma cells. Co-immunoprecipitation experiments showed that HCK was complexed with p-SYK in MYD88Mut BCWM.1 and TMD8 cells, but not in MYD88 wild-type (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 pro-survival signaling generated by aberrant HCK expression in response to MYD88Mut; and help define HCK as an important therapeutic target in MYD88Mut B-cell lymphomas.

Single-cell transcriptome sequencing reveals neutrophil infiltration in degenerative nucleus pulposus tissue

“…Among them, FCGR3A and FCGR3B genes encode Fcγ receptors, which are expressed on neutrophils and bind to immune complexes and activate neutrophils to participate in immune responses. SYK and HCK genes encode tyrosine kinases, which are involved in biological processes such as neutrophil signaling, cell proliferation and differentiation, and cell adhesion [57].The PTPRC (also known as CD45) gene encodes a protein tyrosine phosphatase, which is responsible for regulating the activity of intracellular signaling pathways [58]. ITGAM (also known as CD11b) gene encodes integrin, which interacts with integrin β2 (ITGB2, also known as CD18) to form integrin αMβ2 (also known as Mac-1 or CD11b/CD18) on the surface of neutrophils, which is involved in processes such as cell adhesion, migration and phagocytosis [59].…”

The dual HCK/BTK inhibitor KIN-8194 impairs growth and integrin-mediated adhesion of BTKi-resistant mantle cell lymphoma

“…The SRC-family tyrosine kinase (SFK) hematopoietic cell kinase (HCK), which is predominantly expressed in the hematopoietic cell lineage, has been implicated in various cellular processes including inflammation, proliferation and actin polymerization [17][18][19][20]. We have recently shown that HCK is aberrantly upregulated in MCL patients and that high HCK expression correlates with poor clinical outcome [21].…”