Inhibition of IGF1-R overcomes IGFBP7-induced chemotherapy resistance in T-ALL.
Inhibition of IGF1-R overcomes IGFBP7-induced chemotherapy resistance in T-ALL.
复制标题
IGF1-R的抑制克服了T-ALL中IGFBP7诱导的化学疗法抗性。
DOI：
10.1186/s12885-015-1677-z
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发表时间：
2015-10-08
期刊：
影响因子：
3.8
通讯作者：
Baldus CD
中科院分区：
文献类型：
--
作者：
Bartram I;Erben U;Ortiz-Tanchez J;Blunert K;Schlee C;Neumann M;Heesch S;Baldus CD
T细胞急性淋巴细胞白血病（T-ALL）是一种遗传异质性疾病，需要优化治疗。以前，胰岛素样生长因子结合蛋白7（IGFBP 7）的高表达，IGF系统的成员，被确定为成人T-ALL患者的负预后因素。由于IGFBP 7的异常表达在多种瘤形成中观察到，并且与T-ALL的预后相关，因此我们研究了IGFBP 7在作为T-ALL体外模型的Jurkat和Molt-4细胞中的功能作用。用IGFBP 7过表达载体或作为对照的空载体稳定转染Jurkat和Molt-4细胞。通过WST-1测定评估细胞的增殖，并在BrDU/7-AAD染色后通过流式细胞术测量细胞周期状态。在AnnexinV/7-AAD测定中确定IGFBP 7过表达对细胞生长抑制药物的敏感性的影响。采用Western Blot和流式细胞术检测IGF 1-R蛋白表达。IGF 1-R相关基因表达谱是从来自白血病微阵列创新（MILE）多中心研究的86例T-ALL患者的微阵列基因表达数据中产生的。IGFBP 7转染的Jurkat细胞增殖较少，导致在营养有限的环境中存活时间更长。IGFBP 7转染的Jurkat和Molt-4细胞均表现出在G 0/G1细胞周期期的停滞。此外，Jurkat IGFBP 7转染的细胞对长春新碱和天冬酰胺酶处理具有抗性。IGF 1-R蛋白表达的表面表达和全蛋白测量显示在Jurkat细胞中IGFBP 7转染后受体的丰度降低。有趣的是，IGF 1-R抑制剂NPV-AEW 541的组合恢复了IGFBP 7转染细胞对长春新碱的敏感性。此外，IGF 1-R相关的GEP揭示了T-ALL发病机制的重要驱动因素以及化学抗性和凋亡的调节因子如N 0 TCH 1、BCL-2、PRKCI和TP 53的上调。本研究揭示了IGFBP 7通过G 0/G1阻滞的增殖抑制作用和IGFBP 7对T-ALL中长春新碱和天冬酰胺酶的耐药诱导作用。这些结果为先前观察到的T-ALL患者中IGFBP 7高表达与化疗失败之间的关联提供了模型。由于IGF 1-R抑制可消除对长春新碱的耐药性，因此IGFBP 7可作为可能受益于IGF 1-R抑制剂联合化疗的患者的生物标志物。本文的在线版本（doi：10.1186/s12885-015-1677-z）包含补充材料，可供授权用户使用。
T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease with the need for treatment optimization. Previously, high expression of Insulin-like growth factor binding protein 7 (IGFBP7), a member of the IGF system, was identified as negative prognostic factor in adult T-ALL patients. Since aberrant IGFBP7 expression was observed in a variety of neoplasia and was relevant for prognosis in T-ALL, we investigated the functional role of IGFBP7 in Jurkat and Molt-4 cells as in vitro models for T-ALL. Jurkat and Molt-4 cells were stably transfected with an IGFBP7 over-expression vector or the empty vector as control. Proliferation of the cells was assessed by WST-1 assays and cell cycle status was measured by flow-cytometry after BrDU/7-AAD staining. The effect of IGFBP7 over-expression on sensitivity to cytostatic drugs was determined in AnnexinV/7-AAD assays. IGF1-R protein expression was measured by Western Blot and flow-cytometric analysis. IGF1-R associated gene expression profiles were generated from microarray gene expression data of 86 T-ALL patients from the Microarrays Innovations in Leukemia (MILE) multicenter study. IGFBP7-transfected Jurkat cells proliferated less, leading to a longer survival in a nutrient–limited environment. Both IGFBP7-transfected Jurkat and Molt-4 cells showed an arrest in the G0/G1 cell cycle phase. Furthermore, Jurkat IGFBP7-transfected cells were resistant to vincristine and asparaginase treatment. Surface expression and whole protein measurement of IGF1-R protein expression showed a reduced abundance of the receptor after IGFBP7 transfection in Jurkat cells. Interestingly, combination of the IGF1-R inhibitor NPV-AEW541 restored sensitivity to vincristine in IGFBP7-transfected cells. Additionally, IGF1-R associated GEP revealed an up-regulation of important drivers of T-ALL pathogenesis and regulators of chemo-resistance and apoptosis such as NOTCH1, BCL-2, PRKCI, and TP53. This study revealed a proliferation inhibiting effect of IGFBP7 by G0/G1 arrest and a drug resistance-inducing effect of IGFBP7 against vincristine and asparaginase in T-ALL. These results provide a model for the previously observed association between high IGFBP7 expression and chemotherapy failure in T-ALL patients. Since the resistance against vincristine was abolished by IGF1-R inhibition, IGFBP7 could serve as biomarker for patients who may benefit from therapies including IGF1-R inhibitors in combination with chemotherapy. The online version of this article (doi:10.1186/s12885-015-1677-z) contains supplementary material, which is available to authorized users.