Effect of tyrosine kinase inhibitors on stemness in normal and chronic myeloid leukemia cells

被引:14
作者
Charaf, L. [1 ,2 ,3 ]
Mahon, F-X [1 ,2 ,4 ,5 ]
Lamrissi-Garcia, I. [1 ,2 ,3 ]
Moranvillier, I. [1 ,2 ,3 ]
Beliveau, F. [1 ,3 ]
Cardinaud, B. [1 ,2 ,6 ]
Dabernat, S. [1 ,2 ,3 ,4 ]
de Verneuil, H. [1 ,2 ,3 ,4 ]
Moreau-Gaudry, F. [1 ,2 ,3 ,4 ]
Bedel, A. [1 ,2 ,3 ,4 ]
机构
[1] Inserm U1035, Biotherapies Malad Genet & Canc, 146 Rue Leo Saignat,Batiment TP Zone Sud,4emetage, F-33000 Bordeaux, France
[2] Univ Bordeaux, FR TransBiomed, Bordeaux, France
[3] Lab Excellence GR Ex, Bordeaux, France
[4] CHU Bordeaux, Pole Biol & Pathol, Bordeaux, France
[5] SIRIC BRIO, Inst Bergonie, Bordeaux, France
[6] Inst Polytech Bordeaux, Talence, France
关键词
IMATINIB; CML; QUIESCENT; THERAPY; PROGENITORS; PERSISTENCE; GENERATION; REMISSION; MIGRATION; APOPTOSIS;
D O I
10.1038/leu.2016.154
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Although tyrosine kinase inhibitors (TKIs) efficiently cure chronic myeloid leukemia (CML), they can fail to eradicate CML stem cells (CML-SCs). The mechanisms responsible for CML-SC survival need to be understood for designing therapies. Several previous studies suggest that TKIs could modulate CML-SC quiescence. Unfortunately, CML-SCs are insufficiently available. Induced pluripotent stem cells (iPSCs) offer a promising alternative. In this work, we used iPSCs derived from CML patients (Ph+). Ph+ iPSC clones expressed lower levels of stemness markers than normal iPSCs. BCR-ABL1 was found to be involved in stemness regulation and ERK1/2 to have a key role in the signaling pathway. TKIs unexpectedly promoted stemness marker expression in Ph+ iPSC clones. Imatinib also retained quiescence and induced stemness gene expression in CML-SCs. Our results suggest that TKIs might have a role in residual disease and confirm the need for a targeted therapy different from TKIs that could overcome the stemness-promoting effect caused by TKIs. Interestingly, a similar pro-stemness effect was observed in normal iPSCs and hematopoietic SCs. These findings could help to explain CML resistance mechanisms and the teratogenic side-effects of TKIs in embryonic cells.
引用
收藏
页码:65 / 74
页数:10
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