title: 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 cell 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, an 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 the mitogen-activated protein kinase/extracellular signal-regulated kinase 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 cells, HL60 cells, and blast cells from patients with acute myeloid leukemia-M5 to differentiate, whereas 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 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.
authors.affiliation: State Key Laboratory for Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences, Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China.
authors.forename: Bin-Xia
authors.initials: BX
authors.lastname: Yang
authors.forename: Yong-Juan
authors.initials: YJ
authors.lastname: Duan
authors.forename: Cheng-Ya
authors.initials: CY
authors.lastname: Dong
authors.forename: Fang
authors.initials: F
authors.lastname: Zhang
authors.forename: Wei-Feng
authors.initials: WF
authors.lastname: Gao
authors.forename: Xue-Ying
authors.initials: XY
authors.lastname: Cui
authors.forename: Yong-Min
authors.initials: YM
authors.lastname: Lin
authors.forename: Xiao-Tong
authors.initials: XT
authors.lastname: Ma
mesh_terms: D000208:Acute Disease; D017398:Alternative Splicing; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics*; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014183:Transplantation, Heterologous; D047368:Tumor Burden; D020298:U937 Cells; D000099180:Interleukin-24
chemical_list: D007378:Interleukins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020033:Protein Isoforms; D017382:Reactive Oxygen Species; D013755:Tetradecanoylphorbol Acetate; D000099180:Interleukin-24; C535150:MAPK1 protein, human