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-trans-retinoic acid-induced differentiation of leukemic cell lines and primary AML blasts, whereas miR-638 inhibition caused an opposite phenotype. Consistently, miR-638 overexpression induced G1 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.

中文翻译：

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miR-638通过靶向细胞周期蛋白依赖性激酶2来调节白血病细胞的分化和增殖。

MicroRNA已作为造血细胞和白血病生成的调节剂进行了广泛的研究。我们确定miR-638为白血病细胞骨髓分化和增殖中的新型调节剂。我们发现，miR-638在骨髓细胞而不是淋巴样细胞系中发育上调。此外，在原发性急性髓细胞白血病（AML）原始细胞中观察到显着的miR-638下调，而在原发性AML细胞和经历强制性髓系分化的白血病细胞系中，miR-638的表达显着上调。这些观察结果表明，miR-638可能在骨髓分化中起作用，其失调可能有助于白血病的发生。的确，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发性AML母细胞分化，而miR-638抑制引起相反的表型。一致地，miR-638的过度表达导致G1细胞周期停滞并减少了软琼脂中的菌落形成。发现细胞周期蛋白依赖性激酶2（CDK2）是miR-638的靶基因。CDK2抑制在表型上模仿miR-638的过表达。此外，CDK2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CDK2来调节增殖和骨髓分化，并且可以作为白血病治疗的新靶标或AML诊断和预后的标志物。而miR-638抑制引起相反的表型。一致地，miR-638的过度表达导致G1细胞周期停滞并减少了软琼脂中的菌落形成。发现细胞周期蛋白依赖性激酶2（CDK2）是miR-638的靶基因。CDK2抑制在表型上模仿miR-638的过表达。此外，CDK2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CDK2来调节增殖和骨髓分化，并且可以作为白血病治疗的新靶标或AML诊断和预后的标志物。而miR-638抑制引起相反的表型。一致地，miR-638的过度表达导致G1细胞周期停滞并减少了软琼脂中的菌落形成。发现细胞周期蛋白依赖性激酶2（CDK2）是miR-638的靶基因。CDK2抑制在表型上模仿miR-638的过表达。此外，CDK2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CDK2来调节增殖和骨髓分化，并且可以作为白血病治疗的新靶标或AML诊断和预后的标志物。CDK2抑制在表型上模仿miR-638的过表达。此外，CDK2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CDK2来调节增殖和骨髓分化，并且可以作为白血病治疗的新靶标或AML诊断和预后的标志物。CDK2抑制在表型上模仿miR-638的过表达。此外，CDK2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CDK2来调节增殖和骨髓分化，并且可以作为白血病治疗的新靶标或AML诊断和预后的标志物。