Angiopoietin1 contributes to the maintenance of cell quiescence in EVI1^high leukemia cells

详细信息    查看全文

• 作者：Emi  ; Ichihara ; Kazuko  ; Kaneda ; Yusuke  ; Saito ; Norio  ; Yamakawa ; Kazuhiro  ; Morishita  ; ;   ; ^{kmorishi@medmiyazaki-u.ac.jp}
• 关键词：EVI1 ; AML ; Ang1 ; p18 ; Cell cycle
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2011
• 出版时间：16 December 2011
• 年：2011
• 卷：416
• 期：3-4
• 页码：239-245
• 全文大小：891 K

文摘

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.