ABT-737 increases tyrosine kinase inhibitor-induced apoptosis in chronic myeloid leukemia cells through XIAP downregulation and sensitizes CD34+ CD38- population to imatinib

被引:25
作者
Airiau, Kelly [1 ,2 ]
Mahon, Francois-Xavier [1 ,2 ]
Josselin, Marina [1 ]
Jeanneteau, Marie [2 ]
Turcq, Beatrice [1 ]
Belloc, Francis [1 ,2 ]
机构
[1] Univ Bordeaux Segalen, INSERM 1035, Lab Hematopoiese Leucem & Cibles Therapeut, F-33076 Bordeaux, France
[2] Hop Haut Leveque, CHU Bordeaux, Hematol Lab, Pessac, France
关键词
OUTER MITOCHONDRIAL-MEMBRANE; CHRONIC MYELOGENOUS LEUKEMIA; BCL-2 FAMILY PROTEINS; BCR-ABL; PROTEASE OMI/HTRA2; DRUG-RESISTANCE; DEATH; MECHANISMS; PATHWAY; LINES;
D O I
10.1016/j.exphem.2012.01.004
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Chronic myeloid leukemia (CML) tumorigenicity is driven by the oncogenic BCR-ABL tyrosine kinase. Specific tyrosine kinase inhibitors (TKI) have been designed and are now used for the treatment of CML. These TKI induce apoptosis in leukemic cells in a BIM-dependent mechanism. We hypothesized that an increase in BIM activity could sensitize CML cells to TKI. We blocked the anti-apoptotic proteins of the Bcl-2 family by using ABT-737, a Bcl-2 and Bcl-XL inhibitor. ABT-737 modified Bcl-2 protein interactions toward a pro-apoptotic phenotype. Its combination with TKI resulted in a strong synergism in CML cell lines. The association also induced a large decrease in X-linked inhibitor of apoptosis (XIAP), followed by caspase-3 activation. This XIAP decrease was due to post-translational events. The mitochondrial serine protease HtrA2/Omi was identified as being responsible for this off-target effect. Then, ABT-737 and TKI cooperate at several levels to induce apoptosis of CML cells lines, and the benefit of this association was also observed in CML hematopoietic progenitors. Interestingly, a lethal effect was also observed in the more immature CD34(+)CD38(-) TKI-insensitive population. Combination therapy might by an interesting strategy for the treatment of CML patients. (C) 2012 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.
引用
收藏
页码:367 / 378
页数:12
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