Enhanced sensitivity to inhibition of SHP2, STAT5, and Gab2 expression in chronic myeloid leukemia (CML)

被引:88
作者
Scherr, M
Chaturvedi, A
Battmer, K
Dallmann, I
Schultheis, B
Ganser, A
Eder, M
机构
[1] Hannover Med Sch, Dept Hematol Hemostaseol & Oncol, Hannover, Germany
[2] Heidelberg Univ, Med Clin 3, Univ Hosp Mannheim, D-6800 Mannheim, Germany
关键词
D O I
10.1182/blood-2005-08-3087
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Although targeting the BCR-ABL tyrosine kinase activity by imatinib mesylate has rapidly become first-line therapy, in chronic myelold leukemia (CIVIL), drug resistance suggests that combination therapy directed to a complementing target may significantly improve treatment results. To identify such potential targets, we used lentivirus-mediated RNA interference (RNAi) as a tool for functional genomics in cell lines as well as primary normal and CIVIL CD34(+) cells. In a conditional cell culture model, we demonstrate that RNAi-mediated reduction of SHIP2, STAT5, and Gab2 protein expression inhibits BCR-ABL-dependent but not cytokine-dependent proliferation in a dose-dependent manner. Similarly, colony formation of purified primary CIVIL but not of normal CD34(+) colony-forming cells is specifically reduced by inhibition of SHP2, STAT5, and Gab2 expression, respectively. In addition, coexpression of both anti-BCR-ABL and anti-SHIP2 shIRNAs from a single lentiviral vector induces stronger inhibition of colony formation as compared to either shRNA alone. The data indicate that BCR-ABL expression may affect the function of normal signaling molecules. Targeting these molecules may harbor significant therapeutic potential for the treatment of patients with CIVIL.
引用
收藏
页码:3279 / 3287
页数:9
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