Anlotinib suppresses MLL-rearranged acute myeloid leukemia cell growth through inhibiting SETD1A/AKT-mediated DNA damage response

Abstract Background: Leukemias driven by chromosomal translocation of the mixed-lineage leukemia gene (MLL) are highly prevalent in hematological malignancy. The poor survival rate and lack of an effective targeted therapy for patients with MLL-rearranged (MLL-r) leukemias emphasize an urgent need for improved knowledge and novel therapeutic approaches for these malignancies. In this study, we investigated the potential effectiveness and mechanism of Anlotinib, a novel receptor tyrosine kinase inhibitor, in MLL-r acute myeloid leukemia(AML). Methods: MLL-r AML cell lines were treated with different concentration of Anlotinib, then cell viability, apoptosis and cell cycle were analyzed. Next, the anti-leukemia effect of Anlotinib was further evaluated in vivo in a xenograft model of AML-carrying MLL-rearrangement. Finally, we performed RNA-seq analysis, Gene Set Enrichment Analysis (GSEA) and western bolting to explore the underlying mechanism of the anti-leukemia effect of Anlotinib. Results: Our findings revealed that Anlotinib significantly suppresses the growth, promotes robust apoptosis and induces G2/M arrest in MLL-r AML cells. Moreover, Anlotinib effectively inhibited the growth of MLL-r AML cells in a xenograft murine model. In mechanism, we find that the inhibitive role of Anlotinib in MLL-r AML could be largely attributed to the dysfunction of DNA damage and repair. Furthermore, we confirmed that Anlotinib impaired DNA damage response via inhibiting SETD1A and AKT.