Hematology Department, College of Medicine and Health Sciences, University of Hodiedah, Hodiedah 3730, Yemen.
Advanced Genomics Lab Sdn Bhd, Kota Damansara, Petaling Jaya, Selangor Darul Ehsan 47810, Malaysia.
Oncol Rep. 2019 Mar;41(3):2027-2040. doi: 10.3892/or.2018.6926. Epub 2018 Dec 12.
The t(8;21) translocation is one of the most frequent chromosome abnormalities associated with acute myeloid leukaemia (AML). This abberation deregulates numerous molecular pathways including the ERK signalling pathway among others. Therefore, the aim of the present study was to investigate the gene expression patterns following siRNA‑mediated suppression of RUNX1‑RUNX1T1 and MAPK1 in Kasumi‑1 and SKNO‑1 cells and to determine the differentially expressed genes in enriched biological pathways. BeadChip microarray and gene ontology analysis revealed that RUNX1‑RUNX1T1 and MAPK1 suppression reduced the proliferation rate of the t(8;21) cells with deregulated expression of several classical positive regulator genes that are otherwise known to enhance cell proliferation. RUNX1‑RUNX1T1 suppression exerted an anti‑apoptotic effect through the overexpression of BCL2, BIRC3 and CFLAR genes, while MAPK1 suppression induced apopotosis in t(8;21) cells by the apoptotic mitochondrial changes stimulated by the activity of upregulated TP53 and TNFSF10, and downregulated JUN gene. RUNX1‑RUNX1T1 suppression supported myeloid differentiation by the differential expression of CEBPA, CEBPE, ID2, JMJD6, IKZF1, CBFB, KIT and CDK6, while MAPK1 depletion inhibited the differentiation of t(8;21) cells by elevated expression of ADA and downregulation of JUN. RUNX1‑RUNX1T1 and MAPK1 depletion induced cell cycle arrest at the G0/G1 phase. Accumulation of cells in the G1 phase was largely the result of downregulated expression of TBRG4, CCNE2, FOXO4, CDK6, ING4, IL8, MAD2L1 and CCNG2 in the case of RUNX1‑RUNX1T1 depletion and increased expression of RASSF1, FBXO6, DADD45A and P53 in the case of MAPK1 depletion. Taken together, the current results demonstrate that MAPK1 promotes myeloid cell proliferation and differentiation simultaneously by cell cycle progression while suppresing apoptosis.
t(8;21) 易位是与急性髓系白血病 (AML) 相关的最常见染色体异常之一。这种异常会使许多分子途径失调，包括 ERK 信号通路等。因此，本研究旨在探讨 siRNA 介导的 RUNX1-RUNX1T1 和 MAPK1 抑制对 Kasumi-1 和 SKNO-1 细胞的基因表达模式的影响，并确定富集生物途径中的差异表达基因。BeadChip 微阵列和基因本体分析显示，RUNX1-RUNX1T1 和 MAPK1 的抑制降低了 t(8;21)细胞的增殖率，同时也下调了几个经典的正调控基因的表达，这些基因通常被认为可以增强细胞增殖。RUNX1-RUNX1T1 的抑制通过 BCL2、BIRC3 和 CFLAR 基因的过表达发挥抗凋亡作用，而 MAPK1 的抑制通过上调 TP53 和 TNFSF10 活性刺激的凋亡线粒体变化，以及下调 JUN 基因，诱导 t(8;21)细胞凋亡。RUNX1-RUNX1T1 的抑制通过 CEBPA、CEBPE、ID2、JMJD6、IKZF1、CBFB、KIT 和 CDK6 的差异表达支持髓系分化，而 MAPK1 的耗竭通过 ADA 的上调和 JUN 的下调抑制 t(8;21)细胞的分化。RUNX1-RUNX1T1 和 MAPK1 的耗竭诱导细胞周期停滞在 G0/G1 期。RUNX1-RUNX1T1 耗竭时细胞在 G1 期的积累主要是由于 TBRG4、CCNE2、FOXO4、CDK6、ING4、IL8、MAD2L1 和 CCNG2 的表达下调，而 MAPK1 耗竭时 RASSF1、FBXO6、DADD45A 和 P53 的表达上调所致。综上所述，目前的结果表明，MAPK1 通过细胞周期进展同时促进髓系细胞增殖和分化，同时抑制凋亡。
