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.
