文章：

儿童急性淋巴细胞白血病诱导治疗耐药性的临床前模型

A pre-clinical model of resistance to induction therapy in pediatric acute lymphoblastic leukemia

原文发布日期：2014-08-01

DOI: 10.1038/bcj.2014.52

类型: Original Article

开放获取: 是

英文摘要：

Relapse and acquired drug resistance in T-cell acute lymphoblastic leukemia (T-ALL) remains a significant clinical problem. This study was designed to establish a preclinical model of resistance to induction therapy in childhood T-ALL to examine the emergence of drug resistance and identify novel therapies. Patient-derived T-ALL xenografts in immune-deficient (non-obese diabetic/severe combined immunodeficient) mice were exposed to a four-drug combination of vincristine, dexamethasone (DEX), L-asparaginase and daunorubicin (VXLD). ‘Relapse’ xenografts were characterized by responses to drugs, changes in gene expression profiles and Connectivity Map (CMap) prediction of strategies to reverse drug resistance. Two of four xenografts developed ex vivo and in vivo drug resistance. Both resistant lines showed altered lipid and cholesterol metabolism, yet they had a distinct drug resistance pattern. CMap analyses reinforced these features, identifying the cholesterol pathway inhibitor simvastatin (SVT) as a potential therapy to overcome resistance. Combined ex vivo with DEX, SVT was significantly synergistic, yet when administered in vivo with VXLD it did not delay leukemia progression. Synergy of SVT with established chemotherapy may depend on higher drug doses than are tolerable in this model. Taken together, we have developed a clinically relevant in vivo model of T-ALL suitable to examine the emergence of drug resistance and to identify novel therapies.

摘要翻译： 

T细胞急性淋巴细胞白血病（T-ALL）的复发与获得性耐药仍是重大临床难题。本研究旨在建立儿童T-ALL诱导治疗耐药的临床前模型，以探究耐药机制并识别新型疗法。通过将患者来源的T-ALL异种移植瘤植入免疫缺陷（非肥胖糖尿病/严重联合免疫缺陷）小鼠体内，使其接受长春新碱、地塞米松、L-天冬酰胺酶和柔红霉素四药联合方案治疗。研究通过药物反应、基因表达谱变化及连通性图谱逆向预测耐药逆转策略，对“复发”移植瘤进行表征。四例移植瘤中有两例出现体外与体内双重耐药，这两株耐药细胞系均呈现脂质与胆固醇代谢紊乱，但表现出不同的耐药模式。连通性图谱分析进一步验证这些特征，确定胆固醇通路抑制剂辛伐他汀可作为克服耐药潜力的治疗策略。辛伐他汀与地塞米松在体外联用显示出显著协同效应，但在体内与四药联合方案同时给药时未能延缓白血病进展。辛伐他汀与常规化疗的协同作用可能需要更高剂量药物，这可能超出了该模型的耐受范围。综上，我们成功构建了具有临床相关性的T-ALL体内模型，该模型适用于探究耐药发生机制及发现新型治疗方案。

原文链接：

A pre-clinical model of resistance to induction therapy in pediatric acute lymphoblastic leukemia