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Resistance to farnesyltransferase inhibitors in Bcr/Abl-positive lymphoblastic leukemia by increased expression of a novel ABC transporter homolog ATP11a
Blood ( IF 21.0 ) Pub Date : 2005-08-15 , DOI: 10.1182/blood-2004-09-3655
Bin Zhang 1 , John Groffen , Nora Heisterkamp
Affiliation  

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.

中文翻译:

通过增加新型 ABC 转运蛋白同系物 ATP11a 的表达对 Bcr/Abl 阳性淋巴细胞白血病中的法呢基转移酶抑制剂产生抗性

在用常规化学疗法治疗白血病期间经常出现对细胞毒性药物的抗性。新型抗癌药物,如法呢基转移酶抑制剂 (FTI),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,我们在基质上培养断点簇区/Abelson 鼠白血病 (Bcr/Abl) P190 淋巴母细胞,并使它们对 FTI SCH66336/lonafarnib 具有抗性,以模拟患者出现的耐药性。这些细胞表现出一种新型 ATP(三磷酸腺苷)结合盒 (ABC) 转运蛋白同源基因 ATP11A 的表达水平大大增加(> 100 倍)。我们表明,该基因的过表达可以防止 SCH66336 的影响,而使用小干扰 RNA (siRNA) 敲低内源性 ATP11a 使细胞对这种药物更敏感。对这种 FTI 有抗性的淋巴母细胞也对 FTI-276 和 GGTI-298(2 种其他结构相似的抑制剂)具有更强的抗性。令人惊讶的是,这些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。我们的结果表明,升高水平的 ATP11a 可以保护恶性淋巴细胞白血病细胞免受几种新型小分子信号转导抑制剂的侵害。当考虑用此类药物进行治疗时,确定该基因的表达水平可能具有预后价值。对这种 FTI 有抗性的淋巴母细胞也对 FTI-276 和 GGTI-298(2 种其他结构相似的抑制剂)具有更强的抗性。令人惊讶的是,这些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。我们的结果表明,升高水平的 ATP11a 可以保护恶性淋巴细胞白血病细胞免受几种新型小分子信号转导抑制剂的侵害。当考虑用此类药物进行治疗时,确定该基因的表达水平可能具有预后价值。对这种 FTI 有抗性的淋巴母细胞也对 FTI-276 和 GGTI-298(2 种其他结构相似的抑制剂)具有更强的抗性。令人惊讶的是,这些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。我们的结果表明,升高水平的 ATP11a 可以保护恶性淋巴细胞白血病细胞免受几种新型小分子信号转导抑制剂的侵害。当考虑用此类药物进行治疗时,确定该基因的表达水平可能具有预后价值。细胞对长春新碱仍然敏感。我们的结果表明,升高水平的 ATP11a 可以保护恶性淋巴细胞白血病细胞免受几种新型小分子信号转导抑制剂的侵害。当考虑用此类药物进行治疗时,确定该基因的表达水平可能具有预后价值。细胞对长春新碱仍然敏感。我们的结果表明,升高水平的 ATP11a 可以保护恶性淋巴细胞白血病细胞免受几种新型小分子信号转导抑制剂的侵害。当考虑用此类药物进行治疗时,确定该基因的表达水平可能具有预后价值。
更新日期:2005-08-15
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