Resistance to farnesyltransferase inhibitors in Bcr/Abl-positive lymphoblastic leukemia by increased expression of a novel ABC transporter homolog ATP11a.
Resistance to farnesyltransferase inhibitors in Bcr/Abl-positive lymphoblastic leukemia by increased expression of a novel ABC transporter homolog ATP11a.
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DOI：
10.1182/blood-2004-09-3655
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发表时间：
2005-08
期刊：
影响因子：
20.3
通讯作者：
Bin Zhang;J. Groffen;N. Heisterkamp
中科院分区：
文献类型：
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作者：
Bin Zhang;J. Groffen;N. Heisterkamp
在白血病常规化疗的治疗过程中，经常出现对细胞毒药物的耐药性。新型抗癌药物，如法尼基转移酶抑制剂（FTIs），显示出治疗前景，但细胞是否容易对它们产生耐药性尚不清楚。在这里，我们在基质上生长断点簇区域/Abelson鼠白血病（Bcr/Abl）P190成淋巴细胞，并使它们对FTI SCH 66336/洛那法尼具有抗性，以模拟患者中出现的耐药性。这些细胞表现出一种新的ATP（三磷酸腺苷）结合盒（ABC）转运蛋白同源基因ATP 11 A的表达水平大大增加（> 100倍）。我们发现，该基因的过表达提供了对SCH 66336的保护作用，而使用小干扰RNA（siRNA）敲低内源性ATP 11 a使细胞对这种药物更敏感。对该FTI耐药的淋巴母细胞对FTI-276和GGTI-298（2种其他结构相似的抑制剂）也更具耐药性。令人惊讶的是，细胞也能够在更高浓度的甲磺酸伊马替尼（Bcr/Abl酪氨酸激酶抑制剂）中存活。然而，细胞仍然对长春新碱敏感。我们的研究结果表明，ATP 11 a的水平升高可以保护恶性淋巴细胞白血病细胞对几个新的小分子信号转导抑制剂。当考虑用这类药物治疗时，该基因表达水平的测定可能具有预后价值。
Resistance to cytotoxic drugs frequently emerges during treatment of leukemia with conventional chemotherapy. New classes of anticancer drugs, such as the farnesyltransferase inhibitors (FTIs), show therapeutic promise, but whether cells will easily develop resistance against them is not known. Here, we grew breakpoint cluster region/Abelson murine leukemia (Bcr/Abl) P190 lymphoblasts on stroma and made them resistant to the FTI SCH66336/lonafarnib to model emerging drug resistance in a patient. These cells exhibited greatly increased (> 100-fold) expression levels of a novel ATP (adenosine triphosphate)-binding cassette (ABC) transporter-homologous gene, ATP11A. We showed that overexpression of this gene provided protection against the effects of SCH66336, whereas knockdown of endogenous ATP11a using small interfering RNA (siRNA) made cells more sensitive to this drug. The lymphoblasts that were resistant to this FTI were also more resistant to FTI-276 and to GGTI-298, 2 other structurally similar inhibitors. Surprisingly, the cells were also able to survive higher concentrations of imatinib mesylate, the Bcr/Abl tyrosine kinase inhibitor. However, the cells remained sensitive to vincristine. Our results show that elevated levels of ATP11a can protect malignant lymphoblastic leukemia cells against several novel small molecule signal transduction inhibitors. A determination of the expression levels of this gene may have prognostic value when treatment with such classes of drugs is contemplated.