Glucocorticoid resistance in T-lineage acute lymphoblastic leukaemia is associated with a proliferative metabolism.
Glucocorticoid resistance in T-lineage acute lymphoblastic leukaemia is associated with a proliferative metabolism.
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DOI：
10.1038/sj.bjc.6605072
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发表时间：
2009-06-16
影响因子：
8.8
通讯作者：
Kees, U. R.
中科院分区：
文献类型：
--
作者：
Beesley, A. H.;Firth, M. J.;Ford, J.;Weller, R. E.;Freitas, J. R.;Perera, K. U.;Kees, U. R.
糖皮质激素（GC）是治疗急性淋巴细胞白血病（ALL）的最重要药物之一，然而，尽管其临床重要性，GC细胞毒性和耐药发展的确切机制仍不确定。我们检查了一组T-ALL细胞系的基线特征，以确定在没有预先药物选择的情况下导致GC耐药的因素。转录谱分析表明，T-ALL中的GC抗性与增殖表型相关，涉及糖酵解、氧化磷酸化、胆固醇生物合成和谷氨酸代谢的上调、生长速率增加以及PI3K/AKT/mTOR和MYC信号通路的激活。重要的是，这些转录特征在原发性ALL标本中的存在显著预测了患者的结局。我们的结论是，在淋巴细胞的增殖所需的生物能量途径的激活可能会抑制凋亡的潜力，并抵消GC信号启动的代谢危机。迄今为止，T-ALL中GC耐药和增殖之间的联系可能尚未得到充分认识，因为在当前多药治疗的背景下，这些作用将被掩盖。这些数据还提供了野生型MLL表达改变可能导致GC耐药表型的第一个证据。我们的研究结果保证了选择性代谢抑制剂治疗ALL的持续发展。
Glucocorticoids (GCs) are among the most important drugs for acute lymphoblastic leukaemia (ALL), yet despite their clinical importance, the exact mechanisms involved in GC cytotoxicity and the development of resistance remain uncertain. We examined the baseline profile of a panel of T-ALL cell lines to determine factors that contribute to GC resistance without prior drug selection. Transcriptional profiling indicated GC resistance in T-ALL is associated with a proliferative phenotype involving upregulation of glycolysis, oxidative phosphorylation, cholesterol biosynthesis and glutamate metabolism, increased growth rates and activation of PI3K/AKT/mTOR and MYC signalling pathways. Importantly, the presence of these transcriptional signatures in primary ALL specimens significantly predicted patient outcome. We conclude that in lymphocytes the activation of bioenergetic pathways required for proliferation may suppress the apoptotic potential and offset the metabolic crisis initiated by GC signalling. It is likely that the link between GC resistance and proliferation in T-ALL has not been fully appreciated to date because such effects would be masked in the context of current multiagent therapies. The data also provide the first evidence that altered expression of wild-type MLL may contribute to GC-resistant phenotypes. Our findings warrant the continued development of selective metabolic inhibitors for the treatment of ALL.
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影响因子：
12.4
作者：
Gilardini Montani, MS;Tuosto, L;Piccolella, E
通讯作者：
Piccolella, E
影响因子：
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Holleman, A;den Boer, ML;Pieters, R
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Pieters, R
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Kees, Ursula R.
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通讯作者：
THOMPSON, EB
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作者：
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通讯作者：
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