Differential Contributions of STAT5A and STAT5B to Stress Protection and Tyrosine Kinase Inhibitor Resistance of Chronic Myeloid Leukemia Stem/Progenitor Cells

被引:59
作者
Casetti, Luana [1 ,2 ]
Martin-Lanneree, Severine [1 ,2 ]
Najjar, Imen [1 ,2 ]
Plo, Isabelle [3 ]
Auge, Sylvie [1 ,2 ]
Roy, Lydia [4 ]
Chomel, Jean-Claude [5 ,6 ]
Lauret, Evelyne [1 ,2 ]
Turhan, Ali G. [5 ,6 ]
Dusanter-Fourt, Isabelle [1 ,2 ]
机构
[1] Inst Cochin Genet Mol, Inserm U1016, F-75014 Paris, France
[2] Univ Paris 05, Paris, France
[3] INSERM, U1009, Villejuif, France
[4] CHU, INSERM, CIC0802, Poitiers, France
[5] Univ Poitiers, INSERM, U935, Poitiers, France
[6] CHU, Poitiers, France
关键词
CHRONIC MYELOGENOUS LEUKEMIA; OXIDATIVE STRESS; IMATINIB; ACTIVATION; EXPRESSION; GENE;
D O I
10.1158/0008-5472.CAN-12-3955
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
STAT5 fulfills essential roles in hematopoietic stem cell (HSC) self-renewal and chronic myeloid leukemia (CML), a prototypical stem cell malignancy. However, the specific contributions of the two related genes STAT5A and STAT5B have not been determined. In this study, we used a RNAi-based strategy to establish participation of these genes to CML disease and persistence following targeted therapy. We showed that STAT5A/STAT5B double-knockdown triggers CML cell apoptosis and suppresses both normal and CML HSC long-term clonogenic potential. STAT5A and STAT5B exhibited similar prosurvival activity, but STAT5A attenuation alone was ineffective at impairing growth of normal and CML CD34(+) cells isolated at diagnosis. In contrast, STAT5A attenuation was sufficient to enhance basal oxidative stress and DNA damage of normal CD34(+) and CML cells. Furthermore, it weakened the ability to manage exogenous oxidative stress, increased p53 (TRP53)/CHK-2 (CHEK2) stress pathway activation, and enhanced prolyl hydroxylase domain (PHD)-3 (EGLN3) mRNA expression. Only STAT5A and its transactivation domain-deficient mutant STAT5A Delta 749 specifically rescued these activities. STAT5A attenuation was also active at inhibiting growth of CML CD34(+) cells from patients with acquired resistance to imatinib. Our findings show that STAT5A has a selective role in contributing to stress resistance through unconventional mechanisms, offering new opportunities to eradicate the most primitive and tyrosine kinase inhibitor-resistant CML cells with an additional potential to eradicate persistent stem cell populations. Cancer Res; 73(7); 2052-8. (C)2013 AACR.
引用
收藏
页码:2052 / 2058
页数:7
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