ALPHA-TOCOPHEROL AND G-CSF CHANGE EXPRESSION OF GENES ASSOCIATED WITH DIFFERENTIATION OF K562 CHRONIC MYELOID LEUKEMIA CELLS DOWNREGULATING EMT-ASSOCIATED STEMNESS BIOMARKERS.

L Shvachko, M Zavelevich, M Dybkov, I Gartovska, G Telegeev
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Abstract

Background: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by a block of myeloid differentiation, finally resulting in the uncontrolled expansion of CML stem cells in a phase of blast crisis of the disease. Tyrosine kinase inhibitors (TKI) are effective in delaying CML progression for a long time. Nevertheless, CML cells become resistant to TKI over time. Therefore, the search for alternative and complementary therapies, including differentiation therapy, is currently in the limelight. The aim of the study was to explore the differentiation potential of alpha-tocopherol and granulocyte-colony stimulating factor (G-CSF) by analyzing the gene expression of several factors critical for myeloid differentiation of K562 CML cells, as well as some key leukemic stemness transcription factors.

Materials and methods: The mRNA expression of C/EBPα (CCAAT/enhancer binding protein alpha), neutrophil-granulocytic factor TNAP (tissue non-specific alkaline phosphatase), E-cadherin, SNAIL, OCT4, and PLAP (placental-like alkaline phosphatase) was studied by qRT-PCR in K562 cells exposed to alpha-tocopherol or G-CSF.

Results: K562 cell exposure to alpha-tocopherol or G-CSF resulted in the CEBPB, CDH1, and ALPL gene upregulation. At the same time, down-regulation of EMT-associated markers SNAIL, PLAP, and OCT4 (SNAI1, ALPP, and POU5F1 genes) was demonstrated.

Conclusion: The inverse relationship between expression of the genes of leukemic stemness cell markers SNAIL, OCT4, and PLAP and the genes of myeloid differentiation markers C/EBPα, TNAP, and E-cadherin in K562 cells exposed to alpha-tocopherol or G-CSF suggests the activation of the molecular pattern of myeloid differentiation in this setting.

背景:慢性髓系白血病(Chronic myeloid leukemia, CML)是一种克隆性骨髓增殖性疾病,其特征是髓系分化受阻,最终导致CML干细胞在疾病的细胞危象期不受控制地扩增。酪氨酸激酶抑制剂(TKI)在长期延缓CML进展方面是有效的。然而,随着时间的推移,CML细胞会对TKI产生耐药性。因此,寻找替代和补充疗法,包括分化疗法,目前是人们关注的焦点。本研究旨在通过分析K562 CML细胞髓系分化的几个关键因子以及一些关键的白血病干细胞转录因子的基因表达,探讨α -生育酚和粒细胞集落刺激因子(G-CSF)的分化潜能。材料和方法:采用qRT-PCR方法检测α -生育酚或G-CSF作用下K562细胞C/EBPα (CCAAT/增强子结合蛋白α)、中性粒细胞-粒细胞因子TNAP(组织非特异性碱性磷酸酶)、E-cadherin、SNAIL、OCT4、PLAP(胎盘样碱性磷酸酶)mRNA的表达。结果:K562细胞暴露于α -生育酚或G-CSF可导致CEBPB、CDH1和ALPL基因上调。同时,emt相关标记物SNAIL、PLAP和OCT4 (SNAI1、ALPP和POU5F1基因)下调。结论:暴露于α -生育酚或G-CSF的K562细胞中,白血病干细胞标志物SNAIL、OCT4和PLAP基因与髓细胞分化标志物C/EBPα、TNAP和E-cadherin基因的表达呈负相关,提示在这种情况下髓细胞分化的分子模式被激活。
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