Novel functions for mda-7/IL-24 and IL-24 delE5: regulation of differentiation of acute myeloid leukemic cells

Abstract

Characterizing genes associated with leukemic cells differentiation may provide help for understanding mechanisms on the leukemia differentiation. The aim of this study is to investigate whether the expression of melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) could be induced during leukemia differentiation, and whether mda-7/IL-24 plays a role in leukemia differentiation. We showed that the expression of mda-7/IL-24 and IL-24 delE5, a mda-7/IL-24 splice variant, was induced in U937 and HL60 cells during 12-O-tetradecanoylphorbol-13-acetate (TPA)-mediated monocytic differentiation. Activation of MAPK/ERK pathway was required for their induction. Knockdown of mda-7/IL-24 and IL-24 delE5 resulted in significant inhibition of the monocytic differentiation induced by TPA. More importantly, ectopic overexpression of mda-7/IL-24 and IL-24 delE5 significantly induced U937, HL60 cells, and blast cells from patients with acute myeloid leukemia (AML)-M5 to differentiate, while normal hematopoietic progenitors were not affected. Furthermore, the molecular effector associated with selective differentiation induction by mda-7/IL-24 and IL-24 delE5 may be reactive oxygen species (ROS), and the source of ROS generation was nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Taken together, our results reveal the mechanism by which TPA induces monocytic differentiation, and show for the first time the specific differentiation-inducing effects of mda-7/IL-24 and IL-24 delE5 on human myeloid leukemic cells.