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Abstract：
Acute myeloid leukaemia (AML) is a severe haematological neoplasm that originates from the transformation of haematopoietic stem cells (HSCs) into leukaemic stem cells (LSCs). The bone marrow (BM) microenvironment, particularly that of mesenchymal stromal cells (hMSCs), plays a crucial role in the maintenance of HSCs. In this context, we explored whether alterations in the secretome of hMSCs derived from AML patients (hMSC-AML) could impact HSC gene expression. Proteomic analysis revealed that the secretome of coculture assays with hMSC-AMLs and HSC from healthy donor is altered, with increased levels of secretory leukocyte protease inhibitor (SLPI), a protein associated with important processes for maintenance of the haematopoietic niche that has already been described to be altered in several tumours. Increased SLPI expression was also observed in the BM plasma of AML patients. Transcriptome analysis of HSCs cocultured with hMSC-AML in comparison with HSCs cocultured with hMSC-HD revealed altered expression of SLPI target genes associated with the cell cycle, proliferation, and apoptosis. Important changes were identified, such as increased expression levels of CCNA2, CCNE2, CCND2, CD133 and CDK1 and decreased levels of CDKN2A and IGFBP3, among others. Overall, these findings suggest that the altered secretome of coculture assays with hMSC-AMLs and HSC from healthy donor, particularly increased SLPI expression, can contribute to gene expression changes in HSCs, potentially influencing important molecular mechanisms related to AML development and progression.
摘要：
急性髓性白血病（AML）是一种严重的血液肿瘤，起源于造血干细胞（HSC）向白血病干细胞（LSC）的转化。骨髓（BM）微环境，特别是间充质基质细胞（hMSCs），在HSC的维持中起着至关重要的作用。在这种情况下，我们探讨了源自AML患者的hMSC(hMSC-AML)的分泌组改变是否会影响HSC基因表达.蛋白质组学分析显示，与健康供体的hMSC-AMLs和HSC共培养试验的分泌组发生了改变，随着分泌性白细胞蛋白酶抑制剂（SLPI）水平的增加，一种与维持造血生态位的重要过程相关的蛋白质，已经被描述为在几种肿瘤中发生了改变。在AML患者的BM血浆中也观察到增加的SLPI表达。与hMSC-AML共培养的HSC与hMSC-HD共培养的HSC相比的转录组分析显示与细胞周期相关的SLPI靶基因的表达改变。扩散,和凋亡。确定了重要的变化，如CCNA2、CCNE2、CCND2、CD133和CDK1的表达水平升高，CDKN2A和IGFBP3的水平降低等。总的来说,这些发现表明，与健康供体的hMSC-AMLs和HSC共培养测定的分泌组改变，特别是SLPI表达增加，可以促进HSC基因表达的变化，潜在影响与AML发生和进展相关的重要分子机制。
