Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block
Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block
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DOI：
10.1038/ni1381
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发表时间：
2006-10-01
影响因子：
30.5
通讯作者：
Nerlov, Claus
中科院分区：
文献类型：
--
作者：
Kirstetter, Peggy;Anderson, Kristina;Nerlov, Claus
Wnt信号增加造血干细胞自我更新，并在骨髓和淋巴恶性肿瘤中被激活，表明参与正常和恶性造血。我们在这里报告激活经典Wnt信号在造血系统中通过条件表达的稳定形式的β-连环蛋白。这种强制表达导致与粒细胞-巨噬细胞祖细胞阶段的髓系定型丧失相关的造血衰竭;红细胞分化受阻;淋巴发育中断;以及再生干细胞活性丧失。造血干细胞功能丧失与Cdkn 1a（编码细胞周期抑制剂p21（cdk））、Sfpi 1、Hoxb 4和Bmi 1（分别编码转录因子PU. 1、HoxB 4和Bmi-1）表达降低以及Lin（-）Sca-1（+）c-Kit（+）细胞中整合素表达改变相关，而PU. 1在红系祖细胞中上调。因此，典型Wnt信号传导的组成性激活导致多谱系分化阻断和受损的造血干细胞维持。
Wnt signaling increases hematopoietic stem cell self-renewal and is activated in both myeloid and lymphoid malignancies, indicating involvement in both normal and malignant hematopoiesis. We report here activated canonical Wnt signaling in the hematopoietic system through conditional expression of a stable form of beta-catenin. This enforced expression led to hematopoietic failure associated with loss of myeloid lineage commitment at the granulocyte-macrophage progenitor stage; blocked erythrocyte differentiation; disruption of lymphoid development; and loss of repopulating stem cell activity. Loss of hematopoietic stem cell function was associated with decreased expression of Cdkn1a ( encoding the cell cycle inhibitor p21(cdk)), Sfpi1, Hoxb4 and Bmi1 ( encoding the transcription factors PU.1, HoxB4 and Bmi-1, respectively) and altered integrin expression in Lin(-)Sca-1(+)c-Kit(+) cells, whereas PU.1 was upregulated in erythroid progenitors. Constitutive activation of canonical Wnt signaling therefore causes multilineage differentiation block and compromised hematopoietic stem cell maintenance.