Resistance to Imatinib Mesylate-induced apoptosis in acute lymphoblastic leukemia is associated with PTEN down-regulation due to promoter hypermethylation

被引：32
|
作者：
Montiel-Duarte, Cristina [1 ]
Cordeu, Lucia [1 ]
Agirre, Xabier [1 ]
Roman-Gomez, Jose [2 ]
Jimenez-Velasco, Antonio [3 ]
Jose-Eneriz, Edurne San [1 ]
Garate, Leire [1 ]
Andreu, Enrique J. [1 ]
Calasanz, Maria Jose [4 ]
Heiniger, Anabel [3 ]
Torres, Antonio [2 ]
Prosper, Felipe [1 ]
机构：
[1] Univ Navarra, Serv Hematol, Clin Univ, Div Canc,Area Terapia Celular,Fdn Appl Med Res, Navarra 31008, Spain
[2] Hosp Reina Sofia, Dept Hematol, Cordoba, Spain
[3] Hosp Carlos Haya, Dept Hematol, Malaga, Spain
[4] Univ Navarra, Sch Sci, Dept Genet, E-31080 Pamplona, Spain
来源：
LEUKEMIA RESEARCH | 2008年 / 32卷 / 05期
关键词：
PTEN; Ph+ ALL; Imatinib; PI3K AKT;
D O I：
10.1016/j.leukres.2007.09.005
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
The aim of our study was to determine the potential mechanism(s) implicated in Imatinib resistance in patients with Ph+ ALL. Resistance of Ph+ ALL cells to Imatinib-induced apoptosis was associated with lack of inhibition of Akt phosphorylation. Addition of the PI3K inhibitor LY294002 to Imatinib significantly increased apoptosis of Ph+ ALL cells. Interestingly, expression of PTEN was reduced in Ph+ ALL cells which was due to PTEN promoter hypermethylation. Treatment of Ph+ ALL cells with 5-Aza-2'-deoxycytidine was associated with an increased expression of PTEN and an increase in cell apoptosis. These results suggest that Imatinib resistance in patients with ALL may be dependent at least in part to PTEN down-regulation due to the abnormal promoter hypermethylation and support the potential role of de-methylating agents for the treatment of patients with Ph+ ALL. (C) 2007 Elsevier Ltd. All rights reserved.
引用
收藏
页码：709 / 716
页数：8
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