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

The SRC family kinase (SFK) HCK is transcriptionally upregulated and activated by mutated MYD88 (MYD88(Mut)), a key adaptor for Toll-receptor signaling. HCK activates BTK, AKT, and ERK in MYD88(Mut) lymphomas. SYK, a B-cell receptor (BCR) component, is activated in MYD88(Mut) lymphoma cells. Although the SFK LYN serves as a trigger for SYK activation in MYD88(Mut) ABC DLBCL cells, LYN activity is muted in MYD88(Mut) Waldenstrom macroglobulinemia (WM) cells. We therefore investigated a role for HCK in mediating SYK activation. Overexpression of wild-type (WT) (HCK(WT)) or gatekeeper mutated (HCK(Thr333Met)) HCK in MYD88(Mut) lymphoma cells triggered SYK activation. Conversely, HCK knockdown reduced p-SYK in MYD88(Mut) lymphoma cells. Coimmunoprecipitation experiments showed that HCK was complexed with p-SYK in MYD88(Mut) BCWM.1 and TMD8 cells, but not in MYD88 WT Ramos cells. Rescue experiments in MYD88(Mut) lymphoma cells expressing HCK(Thr333Met) led to persistent HCK and SYK activation and resistance to the HCK inhibitor A419259. Treatment of primary MYD88(Mut) WM cells with A419259 reduced p-HCK and p-SYK expression. Taken together, our findings show that SYK is activated by HCK in MYD88(Mut) B-cell lymphomas cells, broaden the prosurvival signaling generated by aberrant HCK expression in response to MYD88(Mut), and help define HCK as an important therapeutic target in MYD88(Mut) B-cell lymphomas.