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Exp Hematol:白血病对BCR-ABL靶向药物产生耐药的根本原因

来源:生物谷 2014-03-11 20:24

2014年3月12日讯 /生物谷BIOON/--慢性髓性白血病(CML)有特定基因突变,其中一个基因叫做BCR-ABL,针对BCR-ABL突变的药物已经改变了慢性粒细胞白血病的治疗。然而,患者对这些药物可产生耐药性,这会导致他们的癌症复发。

现在,英国Manchester大学科学家测量了慢性粒细胞白血病细胞模型的BCR-ABL基因突变水平。特别是,他们将细胞分为:“粘”性或贴壁细胞,和非贴壁细胞,并找出了两组细胞之间的差异。

博士Richard Byers领导这项研究中,他说:以前的研究已发现,高水平的BCR-ABL突变与耐药性相关,我们希望弄明白整个CML细胞中BCR-ABL的表达有多大差别,尤其是这些贴壁和非贴壁群体之间是否有差异。

发表在Experimental Haematology期刊上的新研究中,该研究小组证明在白血病细胞模型中BCR-ABL表达水平有很大的变化,粘性细胞表达更高水平BCR-ABL,这些粘性细胞对BCR-ABL靶向药物伊马替尼治疗的敏感性低。

Byers博士说:高水平BCR-ABL细胞的数量小,因此通过分析大样本无法检测到这类细胞。但分析单细胞的BCR-ABL水平是重要的,在未来可能在临床中测量单个细胞BCR-ABL水平,帮助我们识别高BCR-ABL的细胞以及更好了解患者如何产生伊马替尼耐药性。(生物谷Bioon.com)

doi:10.1016/j.exphem.2013.11.006
Single-cell analysis of K562 cells: An imatinib-resistant subpopulation is adherent and has upregulated expression of BCR-ABL mRNA and protein

Ehsan Ghayoor Karimiani, Fiona Marriage, Anita J. Merritt, John Burthem, Richard John Byers, Philip J.R. Day

In chronic myeloid leukemia (CML) cells from different stages of maturation may have differential expression of BCR-ABL at both messenger RNA (mRNA) and protein level. However, the significance of such differential expression to clinical disease behavior is unknown. Using the CML-derived, BCR-ABL expressing cell line, K562, distinct plastic-adherent (K562/Adh) and nonadherent (K562/NonAdh) subpopulations were established and then analyzed both as single cells and as bulk cell populations. BCR-ABL mRNA was upregulated in K562/Adh compared with K562/NonAdh cells in both single cell and bulk population analyses (p < 0.0001). Similarly, phosphorylation of BCR protein was upregulated in K562/Adh, compared with K562/NonAdh cells (63.42% vs. 23.1%; p = 0.007), and these two K562 subpopulations were found to express significantly different microRNA species. Furthermore, treatment with the BCR-ABL tyrosine kinase inhibitor, imatinib, reduced cell viability more rapidly in K562/NonAdh compared with K562/Adh cells (p < 0.005) both at single and bulk cell levels. This discovery of an adherent subpopulation of K562 cells with increased BCR-ABL mRNA, increased phosphorylated BCR protein expression, differential microRNA expression, and increased imatinib resistance suggests that a similar subpopulation of cells can also mediate clinical resistance to imatinib during treatment of patients with CML.

 

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