摘要
慢性粒细胞白血病原细胞(CML-CICs)与他们的后代细胞相比能以最高的水平表达混合蛋白BCR-ABL,但是作为下游粒细胞白血病细胞不能以同样的速率进行扩大。此外,来自惰性CML慢性期(CP)的原干细胞克隆在疾病进化到一个致病爆炸危机(BC)时期仍无所改变。与健康的部分相比,最平静的BCR-ABL和CICs表现出保持在一个不寻常的增殖静止的趋势,即长期低能量的可行的状态能够在加强细胞周期的进行和髓样细胞在细胞活素支持下运作时限制对称细胞分裂(自我更新)的频率。在过去的几年,我们和其他人已经提出了营养监测蛋白苏氨酸/丝氨酸激酶GSK3 β(糖原合成酶激酶)作为一种有吸引力的靶点来消灭白血病原细胞而不影响正常造血。除了其本身自我更新过程中的副作用,报道称抑制β-Catenin(Wnt 信号)和c-MYC(Hedgehog 信号)多动性GSK3β的过程对连接能量代谢和干细胞稳态的营养供养很关键。本文综述现有属于GSK3β在正常和恶性造血的生物学意义证据,特别强调了它在CML-CP期和BC转化的作用,也讨论了临床前证据制定GSK3β新型小分子抑制剂的使用作为有潜力的抗白血病制剂。
关键词: 慢性粒细胞白血病,起源白血病细胞,造血干细胞,自我更新,GSK3β,BCRABL,治疗抵抗
图形摘要
Current Drug Targets
Title:Is Going for Cure in CML Targeting Aberrant Glycogen Synthase Kinase 3β?
Volume: 18 Issue: 4
关键词: 慢性粒细胞白血病,起源白血病细胞,造血干细胞,自我更新,GSK3β,BCRABL,治疗抵抗
摘要: Chronic Myelogenous Leukemia (CML)-initiating cells (CICs) express the hybrid oncoprotein BCR-ABL at the highest levels compared to their differentiated progeny but fail to expand at the same rate as downstream leukemic myeloid cells. Moreover, the primitive stem cell clone that originates the indolent CML chronic phase (CP) remains almost invariant as the disease evolves to a fatal blast crisis (BC). Compared to their healthy counterpart, the most dormant BCR-ABL+ CICs show the tendency to remain in a somewhat unusual ‘proliferative quiescence’, i.e. a prolonged low-energy viable state that restrains the frequency of symmetrical (self-renewing) cell divisions while enforcing cell cycle entry and myeloid commitment under cytokine support. Over the past few years, we and others have proposed the nutrient-sensing protein serine/threonine kinase GSK3β (glycogen synthase kinase 3β) as an attractive target to eradicate leukemia-initiating cells while sparing normal haematopoiesis. Beyond its natural negative effects on self-renewal, through the inhibitory phosphorylation of β-Catenin (Wnt signalling) and c-MYC (Hedgehog signalling), hyperactive GSK3β is reportedly crucial to link energy metabolism and nutrient availability to stem cell homeostasis processes. This review will integrate current evidence pertaining to the biological relevance of GSK3β in normal and malignant haematopoiesis, with particular emphasis on its role(s) at the CML CP stage and BC transformation. Preclinical evidence earmarking the use of novel small-molecule inhibitors of GSK3β as promsing anti-leukemia agents are also discussed.
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Cite this article as:
Is Going for Cure in CML Targeting Aberrant Glycogen Synthase Kinase 3β?, Current Drug Targets 2017; 18 (4) . https://dx.doi.org/10.2174/1389450117666160817151723
DOI https://dx.doi.org/10.2174/1389450117666160817151723 |
Print ISSN 1389-4501 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5592 |
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