Autophagy contributes to dasatinib-induced myeloid differentiation of human acute myeloid leukemia cells.

ABSTRACT

A breakthrough in clinical oncology was achieved as All-trans-retinoic acid (ATRA) sparked intensive differentiation therapy research. However, differentiation therapy is limited because ATRA is the sole efficient agent. Dasatinib is reported to induce myeloid differentiation of acute myeloid leukemia (AML) cells in vitro, but its mechanism remains unclear. Furthermore, the ability of dasatinib to cause differentiation of AML cells has not yet been proven. We assessed the contribution of autophagy to dasatinib-induced differentiation of AML cells. We found that dasatinib induces myeloid differentiation of AML cells accompanied with autophagy induction. Pharmacological inhibition of autophagy by 3-MA, Wortmannin, LY294002 and chloroquine block dasatinib-induced AML cell differentiation, whereas the induction of autophagy by rapamycin enhances AML cell differentiation. Our results suggest that retinoic acid receptors alpha (RARα) may not be involved in dasatinib-induced differentiation. In addition, we further illustrated that even low concentration of dasatinib can enhance ATRA-induced differentiation capability through initiation of autophagy. Taken together, we conclude that autophagy enhances the dasatinib-induced differentiation, which may provide theoretical support for developing dasatinib as a promising strategy for future differentiation therapy in AML patients.