Inhibition of Src family kinases enhances retinoic acid-induced gene expression and myeloid differentiation
Inhibition of Src family kinases enhances retinoic acid-induced gene expression and myeloid differentiation
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DOI：
10.1158/1535-7163.mct-07-0514
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发表时间：
2007-12-01
影响因子：
5.7
通讯作者：
Johnson, Daniel E.
中科院分区：
文献类型：
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作者：
Miranda, Michelle B.;Redner, Robert L.;Johnson, Daniel E.
维甲酸(RA)治疗急性早幼粒细胞白血病可导致白血病细胞分化和临床缓解。然而，调节RA诱导的髓系分化的细胞因素在很大程度上是未知的，其他形式的急性髓系白血病(AML)对这种分化治疗没有反应。对正向或负向调节RA诱导分化的分子有更深入的了解，有助于开发更有效的分化治疗方法。在这项研究中，我们研究了Src家族激酶(SFK)在调节RA诱导的基因表达和髓系分化中的潜在作用。我们报道，抑制SFKs显著增强了RA诱导的髓系细胞系和原代AML细胞的分化，这是通过细胞表面标志的流式细胞术分析、形态分析和四氮氮蓝还原来评估的。此外，抑制视黄酸受体(RAR)靶基因编码CCAAT/增强子结合蛋白epsilon(C/EBP epsilon)、PU.1、细胞间黏附分子-1(ICAM1)和组织蛋白酶D的表达增强。此外，有活性的Src抑制RAR依赖的转录，而死于激酶的Src几乎没有影响。这些研究首次证明SFK对RA诱导的基因表达和髓系分化具有负性调节作用，并提示SFK抑制和RA治疗联合应用对AML的治疗可能是有益的。
Treatment of acute promyelocytic leukemia with retinoic acid (RA) results in differentiation of the leukemic cells and clinical remission. However, the cellular factors that regulate RA-induced myeloid differentiation are largely unknown, and other forms of acute myelogenous leukemia (AML) do not respond to this differentiation therapy. A greater understanding of the molecules that positively or negatively regulate RA-induced differentiation should facilitate the development of more effective differentiation therapies. In this study, we investigated the potential role of Src family kinases (SFK) in the regulation of RA-induced gene expression and myeloid differentiation. We report that inhibition of SFKs markedly enhanced RA-induced differentiation in myeloid cell lines and primary AML cells, as assessed by flow-cytometric analysis of cell surface markers, morphologic analysis, and nitroblue tetrazolium reduction. In addition, inhibition of SFKs enhanced expression from retinoic acid receptor (RAR) target genes encoding CCAAT/enhancer binding protein epsilon (C/EBP epsilon), PU.1, intercellular adhesion molecule-1 (ICAM1), and cathepsin D. Moreover, a constitutively active Src inhibited RAR-dependent transcription, whereas a kinase-dead Src exerted little effect. These studies provide the first demonstration that SFKs act to negatively regulate RA-induced gene expression and myeloid differentiation and suggest that the combination of SFK inhibition and RA treatment may be therapeutically beneficial in AML.