Gene profile of myeloid-derived suppressive cells from the bone marrow of lysosomal acid lipase knock-out mice.
Gene profile of myeloid-derived suppressive cells from the bone marrow of lysosomal acid lipase knock-out mice.
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DOI：
10.1371/journal.pone.0030701
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Du H
中科院分区：
文献类型：
--
作者：
Yan C;Ding X;Dasgupta N;Wu L;Du H
溶酶体酸性脂肪酶（LAL）控制髓系细胞的发育和稳态。溶酶体酸性脂肪酶（LAL）功能的丧失导致髓源性抑制细胞（MDSC）的扩增，导致骨髓增生性肿瘤。Affyscore基因芯片微阵列分析确定了LAL敲除（lal−/−）小鼠Ly 6 G+髓系细胞的详细内在缺陷。免疫途径分析揭示了哺乳动物雷帕霉素靶（mTOR）信号传导的激活，其作为营养/能量/氧化还原传感器起作用，并控制细胞生长、细胞周期进入、细胞存活和细胞运动。LAL功能的丧失导致大GT3和小GT3信号转导途径的重大改变。骨髓中的lal−/− Ly 6 G+髓样细胞表现出与细胞周期蛋白和细胞周期蛋白依赖性激酶（cdk）基因的上调相关的细胞增殖的显著增加。由于多个组蛋白簇基因、着丝粒蛋白基因和染色体修饰基因的表达增加，表观遗传微环境发生了显著变化。生物能量途径的基因表达，包括糖酵解、有氧糖酵解、线粒体氧化磷酸化和呼吸链蛋白，也增加了，而在lal−/− Ly 6 G+骨髓细胞中线粒体功能受损。这些细胞中活性氧（ROS）的浓度显著增加，伴随着一氧化氮/ROS产生基因的上调。这项全面的基因图谱研究首次使用lal−/−小鼠模型鉴定和定义了参与骨髓谱系细胞向MDSC转化的重要基因通路。
Lysosomal acid lipase (LAL) controls development and homeostasis of myeloid lineage cells. Loss of the lysosomal acid lipase (LAL) function leads to expansion of myeloid-derived suppressive cells (MDSCs) that cause myeloproliferative neoplasm. Affymetrix GeneChip microarray analysis identified detailed intrinsic defects in Ly6G+ myeloid lineage cells of LAL knock-out (lal−/−) mice. Ingenuity Pathway Analysis revealed activation of the mammalian target of rapamycin (mTOR) signaling, which functions as a nutrient/energy/redox sensor, and controls cell growth, cell cycle entry, cell survival, and cell motility. Loss of the LAL function led to major alteration of large GTPase and small GTPase signal transduction pathways. lal−/− Ly6G+ myeloid cells in the bone marrow showed substantial increase of cell proliferation in association with up-regulation of cyclin and cyclin-dependent kinase (cdk) genes. The epigenetic microenvironment was significantly changed due to the increased expression of multiple histone cluster genes, centromere protein genes and chromosome modification genes. Gene expression of bioenergetic pathways, including glycolysis, aerobic glycolysis, mitochondrial oxidative phosphorylation, and respiratory chain proteins, was also increased, while the mitochondrial function was impaired in lal−/− Ly6G+ myeloid cells. The concentration of reactive oxygen species (ROS) was significantly increased accompanied by up-regulation of nitric oxide/ROS production genes in these cells. This comprehensive gene profile study for the first time identifies and defines important gene pathways involved in the myeloid lineage cells towards MDSCs using lal−/− mouse model.
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