Acute myeloid leukemia-derived bone marrow mesenchymal cells exhibit improved support for leukemic cell proliferation.

Mariane Cristina do Nascimento, Diego A Pereira-Martins, João Agostinho Machado-Neto, Eduardo M Rego
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Abstract

Introduction: The bone marrow (BM) microenvironment plays a significant role in acute myeloid leukemia (AML) genesis and there is evidence that BM mesenchymal stromal cells (BMMSCs) can support leukemia progenitor cell proliferation and survival and provide resistance to cytotoxic therapies.

Hypothesis and method: Nevertheless, currently unknown are the relevance of the spatial localization of AML cells relative to the BMMSCs and whether BMMSCs from patients with AML and healthy subjects have similar properties. To address these issues, we performed a differential gene expression analysis using RNA-sequencing data generated from healthy donors (HDs) and leukemic BMMSCs.

Results: The Gene Set Enrichment Analysis (GSEA) revealed that leukemic BMMSCs were associated with the terms "positive regulation of cell cycle", "angiogenesis" and "signaling by the estimated glomerular filtration rate (eGFR)", whereas healthy donor (HD)-derived BMMSCs were associated with "programmed cell death in response to the reactive oxygen species (ROS)", "negative regulation of the cytochrome C from the mitochondria" and "interferon signaling". Next, we evaluated the mitochondrial superoxide production in AML cells in a co-culture layered model. The superoxide production was reduced in leukemic cells in close contact (adhered to the surface or beneath the cell layer) with BMMSCs, indicating lower oxidative stress.

Conclusion: Taken together, our results suggest that AML-derived BMMSCs are transcriptionally rewired and can reduce the metabolic stress of leukemic cells.

急性髓性白血病衍生的骨髓间充质细胞对白血病细胞增殖有更好的支持作用。
导言:骨髓(BM)微环境在急性髓性白血病(AML)的发生中起着重要作用,有证据表明骨髓间充质基质细胞(BMMSCs)可支持白血病祖细胞的增殖和存活,并提供对细胞毒疗法的抵抗力:然而,目前尚不清楚AML细胞相对于BMMSCs的空间定位的相关性,以及AML患者和健康人的BMMSCs是否具有相似的特性。为了解决这些问题,我们利用健康供体(HDs)和白血病 BMMSCs 的 RNA 序列数据进行了差异基因表达分析:基因组富集分析(Gene Set Enrichment Analysis,GSEA)显示,白血病 BMMSCs 与 "细胞周期的正向调节"、"血管生成 "和 "估计肾小球滤过率(eGFR)的信号转导 "相关,而健康供体(HD)来源的 BMMSCs 则与 "活性氧(ROS)导致的细胞程序性死亡"、"线粒体细胞色素 C 的负向调节 "和 "干扰素信号转导 "相关。接下来,我们在共培养分层模型中评估了急性髓细胞线粒体超氧化物的产生。与 BMMSCs 密切接触(粘附在细胞表面或细胞层下)的白血病细胞超氧化物产生减少,表明氧化应激降低:综上所述,我们的研究结果表明,急性髓细胞衍生的 BMMSCs 可进行转录重排,并能降低白血病细胞的代谢压力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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