Inhibition of DOCK1 suppresses Notch signalling pathway and impairs leukaemogenesis

Dedicator of cytokinesis 1 (DOCK1), a guanine nucleotide exchange factor for the small GTPase Rac, has been implicated in various biological processes, but its pathological roles in acute myeloid leukaemia (AML) remain unexplored. In this study, we analysed the clinical impacts of DOCK1 expression in 341 patients with de novo non-M3 AML treated with standard chemotherapy. The results showed that high DOCK1 expression is an independent adverse prognostic factor. Consistent with this, experiments using cell lines, xenografts and Dock1 conditional-knockout mice all demonstrated the pro-survival effects of DOCK1 in AML cells. This observation was corroborated by findings that the absence of Dock1 ameliorated the MN1-induced AML phenotypes. Transcriptome analyses demonstrated an association between DOCK1 expression and upregulated Notch signalling, and the causal relationship was supported by cell line experiments. Furthermore, single-cell RNA sequencing of MN1-induced mouse AML cells revealed a unique cluster with upregulated stem cell functions and Hes1, a Notch target, in the Dock1 wild type but not knockout background. These findings underscore the clinical and pathogenic significance of DOCK1 in AML and support its potential as a therapeutic target.