Anlotinib Potentially Eliminates Leukemia Stem Cells and Modulates the Chemosensitivity via Inhibiting JAK2-STAT3/5 Signaling

Abstract Leukemia stem cells (LSCs) remain as the critical barrier to cure of acute myeloid leukemia (AML) due to its chemoresistance. Here, we explore the role anlotinib -a multiple tyrosine kinases inhibitor in killing LSCs and regulating the chemoresistance. We found anlotinib could effectively induce apoptosis of LSC-like cells as well as primary CD34+ AML LSCs while sparing the normal mononuclear cells in vitro. The anti-leukemia activity of anlotinib was also confirmed in the mice model with Kasumi-1 cells; we further found that anlotinib could impair the regeneration capacity of LSCs in the patient-derived leukemia xenograft mouse model. Mechanistically, anlotinib could not only inhibit phosphorylation of c-kit and JAK2 /STAT3 and STAT5 but also downregulate STAT3 and STAT5 expression. In addition, anlotinib downregulated the anti-apoptotic protein Bcl-2 and Bcl-xl and upregulated Bax, thereby enhancing the sensitivity of LSCs to idarubicin in vitro. In conclusion, our results demonstrated anlotinib showed anti-LSCs activity and enhanced the chemosensitivity via inhibiting JAK2/STAT signaling in preclinical study and provided a rational basis for combinatory strategies that invoving anlotinib and idarubicin.