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首页> 外文期刊>Nature >Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy
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Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy

机译：糖原合酶激酶3在MLL白血病维持和靶向治疗中的作用

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Glycogen synthase kinase 3 (GSK3) is a multifunctional serine/threonine kinase that participates in numerous signalling pathways involved in diverse physiological processes. Several of these pathways are implicated in disease pathogenesis, which has prompted efforts to develop GSK3-specific inhibitors for therapeutic applications. However, before now, there has been no strong rationale for targeting GSK3 in malignancies. Here we report pharmacological, physiological and genetic studies that demonstrate an oncogenic requirement for GSK3 in the maintenance of a specific subtype of poor prognosis human leukaemia, genetically defined by mutations of the MLL proto-oncogene. In contrast to its previously characterized roles in suppression of neoplasia-associated signalling pathways, GSK3 paradoxically supports MLL leukaemia cell proliferation and transformation by a mechanism that ultimately involves destabilization of the cyclin-dependent kinase inhibitor p27~(kip1). Inhibition of GSK3 in a preclinical murine model of MLL leukaemia provides promising evidence of efficacy and earmarks GSK3 as a candidate cancer drug target.
机译：糖原合酶激酶3（GSK3）是一种多功能的丝氨酸/苏氨酸激酶，它参与了涉及多种生理过程的众多信号传导途径。这些途径中的几种与疾病发病机理有关，这促使人们努力开发用于治疗应用的GSK3特异性抑制剂。但是，在此之前，尚无针对恶性肿瘤中靶向GSK3的强烈理由。在这里，我们报告了一些药理，生理和遗传研究，这些研究表明，在维持预后不良的人类白血病的特定亚型中，GSK3的致癌作用需要通过MLL原癌基因的突变进行遗传定义。与它先前在抑制肿瘤相关信号通路中所起的作用相反，GSK3通过最终涉及细胞周期蛋白依赖性激酶抑制剂p27〜（kip1）失稳的机制自相矛盾地支持MLL白血病细胞的增殖和转化。在MLL白血病的临床前鼠模型中抑制GSK3提供了有希望的功效证据，并指定了GSK3作为候选的癌症药物靶标。

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