Angiopoietin1 contributes to the maintenance of cell quiescence in EVI1high leukemia cells
Copyright policy )Angiopoietin1 contributes to the maintenance of cell quiescence in EVI1high leukemia cells
Ecotropic viral integration site-1 (EVI1) is an oncogenic transcription factor in human acute myeloid leukemia (AML) associated with poor prognosis. Because the drug-resistance of leukemia cells is partly dependent on cell quiescence in the bone marrow niche, EVI1 may be involved in cell cycle regulation in leukemia cells. As a candidate regulator of the cell cycle in leukemia cells with high EVI1 expression (EVI1(high)), we analyzed angiopoietin1 (Ang1), which is a down-regulated gene in EVI1-deficient mice and is involved in the quiescence of hematopoietic stem cells. The results of real-time PCR analyses showed that Ang1 is highly expressed in leukemia cell lines and primary AML cells with EVI1(high) expression. Introduction of shRNA against EVI1 into EVI1(high) leukemia cells down-regulated Ang1 expression. Moreover, knockdown of Ang1 in EVI1(high) leukemia cells promoted cell cycle progression and down-regulated the CDK inhibitor p18 (INK4c). Treatment with a decoy Tie2/Fc protein also down-regulated the expression of p18. These results suggest that Ang1/Tie2 signaling may suppress cell cycle progression via maintenance of G0/G1 phase through up-regulation of p18 expression. This mechanism may help to maintain EVI1(high) leukemia cells in the bone marrow niche and promote resistance to anti-cancer drugs.
- University of Miyazaki Japan
Gene Expression Regulation, Leukemic, Cell Cycle, MDS1 and EVI1 Complex Locus Protein, DNA-Binding Proteins, Leukemia, Myeloid, Acute, Mice, Drug Resistance, Neoplasm, Cell Line, Tumor, Gene Knockdown Techniques, Proto-Oncogenes, Angiopoietin-1, Animals, Cyclin-Dependent Kinase Inhibitor p18, Humans, Drug Screening Assays, Antitumor, Transcription Factors
Gene Expression Regulation, Leukemic, Cell Cycle, MDS1 and EVI1 Complex Locus Protein, DNA-Binding Proteins, Leukemia, Myeloid, Acute, Mice, Drug Resistance, Neoplasm, Cell Line, Tumor, Gene Knockdown Techniques, Proto-Oncogenes, Angiopoietin-1, Animals, Cyclin-Dependent Kinase Inhibitor p18, Humans, Drug Screening Assays, Antitumor, Transcription Factors
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