...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Molecular and Cellular Biology >Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets
【24h】

Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets

机译：髓系白血病中KLF4的表达失控通过MicroRNA和基因靶标改变细胞的增殖和分化

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

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 Krüppel-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.
机译：急性髓细胞性白血病（AML）的特征是造血祖细胞的增殖增加和分化受阻，部分是由髓样转录因子表达的改变介导的。 AML中已观察到Krüppel样因子4（KLF4）表达下降，但是KLF4下降如何导致AML发病机理尚不清楚。我们证明在具有各种细胞遗传学异常的AML患者样品中KLF4表达下降，证实KLF4过表达促进髓样细胞分化并抑制AML细胞系中的细胞增殖，并确定KLF4的新靶标。我们已经证明，AML中的microRNA 150（miR-150）表达降低，并且重新引入miR-150表达可诱导骨髓分化并抑制AML细胞的增殖。我们显示，KLF家族DNA结合位点对于miR-150启动子活性是必需的，并且KLF2或KLF4过表达诱导miR-150表达。单独使用miR-150沉默或与CDKN1A（众所周知的KLF4靶标）沉默相结合，并不能完全逆转KLF4介导的作用。基因表达谱分析和验证确定了假定的KLF4调控基因，包括KLF4过表达细胞中MYC减少和下游MYC调控基因表达。我们的发现表明，降低的KLF4表达通过调控包含miR-150，CDKN1A和MYC的基因和microRNA网络介导抗白血病作用，并为增加KLF4表达的治疗策略提供了机械支持。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号