Statins induce monocytic differentiation in acute myeloid leukemia cells through the <scp>KLF4</scp> / <scp>DPYSL2A</scp> axis

Acute myeloid leukemia (AML) is a bone marrow malignancy characterized by arrested early-stage hematopoietic precursor development. Differentiation therapy, which induces terminal differentiation of immature leukemic cells, is less toxic than standard intensive chemotherapy and a promising treatment strategy for AML. Despite the success of all-trans retinoic acid and arsenic trioxide in treating acute promyelocytic leukemia (APL), effective differentiation therapy for non-APL AML has not been established. We previously demonstrated that dihydropyrimidinase-like 2A (DPYSL2A) is crucial for the monocytic differentiation of AML cells. In this study, analysis using the Comparative Toxicogenomics Database identified statins, which are well-known cholesterol-lowering drugs, as potential compounds that upregulate DPYSL2A expression in a Krüppel-like factor 4 (KLF4)-dependent manner. Most of the tested statins promoted the monocytic differentiation of non-APL AML cells, leading to rapid apoptosis. The statin-induced effects were reversed by mevalonate (MVA) supplementation, indicating dependence on MVA pathway inhibition. Furthermore, the inhibition of protein farnesylation, a downstream process of the MVA pathway, mimicked the statin-induced effects, suggesting that farnesylation suppression is essential for statin-induced KLF4/DPYSL2A expression and monocytic differentiation. These findings may help develop more effective differentiation therapies for patients with non-APL AML.