Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets
Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets
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DOI：
10.1128/mcb.00712-15
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发表时间：
2016-02-01
影响因子：
5.3
通讯作者：
Oehler, Vivian G.
中科院分区：
文献类型：
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作者：
Morris, Valerie A.;Cummings, Carrie L.;Oehler, Vivian G.
急性髓性白血病（AML）的特征在于部分地由髓样转录因子表达改变介导的造血祖细胞的增殖增加和分化受阻。在AML中观察到Kruppel样因子4（KLF 4）表达降低，但KLF 4的降低如何促进AML发病机制在很大程度上是未知的。我们证明了KLF 4表达降低AML患者样本与各种细胞遗传学畸变，证实KLF 4过表达促进骨髓分化和抑制细胞增殖的AML细胞系，并确定新的KLF 4的目标。我们已经证明，microRNA 150（miR-150）表达在AML中降低，重新引入miR-150表达诱导骨髓分化并抑制AML细胞增殖。我们发现，KLF家族DNA结合位点是miR-150启动子活性所必需的，KLF 2或KLF 4过表达诱导miR-150表达。miR-150沉默，单独或与CDKN 1A（一种充分描述的KLF 4靶点）沉默联合，不能完全逆转KLF 4介导的效应。基因表达谱分析和验证确定了推定的KLF 4调节基因，包括KLF 4过表达细胞中MYC和下游MYC调节基因表达的降低。我们的研究结果表明，KLF 4表达减少通过调控基因和microRNA网络介导抗白血病作用，包含miR-150，CDKN 1A和MYC，并为增加KLF 4表达的治疗策略提供机制支持。
Acute myeloid leukemia (AML) is characterized by increased proliferation and blocked differentiation of hematopoietic progenitors mediated, in part, by altered myeloid transcription factor expression. Decreased Kruppel-like factor 4 (KLF4) expression has been observed in AML, but how decreased KLF4 contributes to AML pathogenesis is largely unknown. We demonstrate decreased KLF4 expression in AML patient samples with various cytogenetic aberrations, confirm that KLF4 overexpression promotes myeloid differentiation and inhibits cell proliferation in AML cell lines, and identify new targets of KLF4. We have demonstrated that microRNA 150 (miR-150) expression is decreased in AML and that reintroducing miR-150 expression induces myeloid differentiation and inhibits proliferation of AML cells. We show that KLF family DNA binding sites are necessary for miR-150 promoter activity and that KLF2 or KLF4 overexpression induces miR-150 expression. miR-150 silencing, alone or in combination with silencing of CDKN1A, a well-described KLF4 target, did not fully reverse KLF4-mediated effects. Gene expression profiling and validation identified putative KLF4-regulated genes, including decreased MYC and downstream MYC-regulated gene expression in KLF4-overexpressing cells. Our findings indicate that decreased KLF4 expression mediates antileukemic effects through regulation of gene and microRNA networks, containing miR-150, CDKN1A, and MYC, and provide mechanistic support for therapeutic strategies increasing KLF4 expression.