miR-638 Regulates Differentiation and Proliferation in Leukemic Cells by Targeting Cyclin-dependent Kinase 2
miR-638 Regulates Differentiation and Proliferation in Leukemic Cells by Targeting Cyclin-dependent Kinase 2
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miR-638 通过靶向细胞周期蛋白依赖性激酶 2 调节白血病细胞的分化和增殖。
DOI：
10.1074/jbc.m114.599191
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发表时间：
2015-01-16
影响因子：
4.8
通讯作者：
Huang, Zan
中科院分区：
文献类型：
--
作者：
Lin, Yi;Li, Dengju;Huang, Zan
MicroRNA作为造血和白血病发生的调节因子已被广泛研究。我们鉴定了miR-638作为白血病细胞髓样分化和增殖的新调节因子。我们发现miR-638在髓系而非淋巴系细胞中发育上调。此外，在原发性急性髓性白血病（AML）母细胞中观察到显著的miR-638下调，而在原发性AML母细胞和经历强制髓样分化的白血病细胞系中，miR-638表达显著上调。这些观察结果表明，miR-638可能在骨髓分化中发挥作用，其调节异常可能导致白血病发生。事实上，miR-638的异位表达促进了佛波醇12-肉豆蔻酸酯13-乙酸酯或全反式维甲酸诱导的白血病细胞系和原代AML母细胞的分化，而miR-638抑制引起相反的表型。同样，miR-638过表达诱导G（1）细胞周期停滞，并减少软琼脂中的集落形成。发现细胞周期蛋白依赖性激酶2（CDK 2）是miR-638的靶基因。CDK 2抑制在表型上模拟了miR-638的过表达。此外，CDK 2的强制表达恢复了miR-638抑制的增殖和集落形成能力。我们的数据表明，miR-638通过靶向CDK 2调节增殖和髓系分化，并可能作为白血病治疗的新靶点或AML诊断和预后的标志物。
MicroRNAs have been extensively studied as regulators of hematopoiesis and leukemogenesis. We identified miR-638 as a novel regulator in myeloid differentiation and proliferation of leukemic cells. We found that miR-638 was developmentally up-regulated in cells of myeloid but not lymphoid lineage. Furthermore, significant miR-638 down-regulation was observed in primary acute myeloid leukemia (AML) blasts, whereas miR-638 expression was dramatically up-regulated in primary AML blasts and leukemic cell lines undergoing forced myeloid differentiation. These observations suggest that miR-638 might play a role in myeloid differentiation, and its dysregulation may contribute to leukemogenesis. Indeed, ectopic expression of miR-638 promoted phorbol 12-myristate 13-acetate- or all-transretinoic acid-induced differentiation of leukemic cell lines and primary AML blasts, whereas miR-638 inhibition caused an opposite phenotype. Consistently, miR-638 overexpression induced G(1) cell cycle arrest and reduced colony formation in soft agar. Cyclin-dependent kinase 2 (CDK2) was found to be a target gene of miR-638. CDK2 inhibition phenotypically mimicked the overexpression of miR-638. Moreover, forced expression of CDK2 restored the proliferation and the colony-forming ability inhibited by miR-638. Our data suggest that miR-638 regulates proliferation and myeloid differentiation by targeting CDK2 and may serve as a novel target for leukemia therapy or marker for AML diagnosis and prognosis.