肿瘤微环境（TME）是一个支持性环境，负责促进肿瘤细胞的生长和增殖。目前的研究表明，骨髓间充质干细胞（BM-MSCs）作为TME中关键的基质细胞，可以促进肿瘤的恶性发展。然而，在成人B细胞急性淋巴细胞白血病（B-ALL）微环境中，BM-MSCs受白血病细胞诱导产生了何种变化仍然不明确。本研究通过构建BM-MSCs-白血病细胞共培养系统来模拟白血病微环境。通过体外细胞实验、体内小鼠模型实验、慢病毒转染和转录组测序分析，研究了BM-MSCs在白血病复合体中的可能变化以及促进白血病进展的潜在因子。在白血病复合体中，白血病细胞降低了MSCs向脂肪化和骨化亚型分化的能力，并促进了MSCs的衰老和细胞周期阻滞。同时，与单培养的MSCs相比，白血病复合体中MSCs的基因表达谱发生了显著变化。这些差异基因富集于细胞周期、细胞分化、DNA复制以及一些促进肿瘤的生物功能，包括蛋白质磷酸化、细胞迁移和血管生成。此外，受干扰素激活的基因（IFI6）在白血病复合体中的MSCs中高度表达。IFI6显著促进了白血病细胞的体内外增殖。从机制上讲，IFI6可能通过刺激SDF-1 / CXCR4轴引发下游ERK信号通路，从而促进白血病细胞的增殖。进一步的RNA测序分析表明，在MSCs中高表达IFI6在一定程度上影响了白血病细胞的基因表达谱和生物功能。白血病复合体中的BM-MSCs具有不同程度的生物特征和基因表达谱的变化。BM-MSCs中IFI6的过表达可能是促进B-ALL细胞增殖的关键因素，这种效应可能通过SDF-1/CXCR4/ERK信号刺激来实现。针对IFI6或相关信号通路可能是减少白血病细胞增殖的重要措施。© 2023. BioMed Central Ltd., part of Springer Nature.

The tumor microenvironment (TME) is a supportive environment responsible for promoting the growth and proliferation of tumor cells. Current studies have revealed that the bone marrow mesenchymal stem cells (BM-MSCs), a type of crucial stromal cells in the TME, can promote the malignant progression of tumors. However, in the adult B-cell acute lymphoblastic leukemia (B-ALL) microenvironment, it is still uncertain what changes in BM-MSCs are induced by leukemia cells.In this study, we mimicked the leukemia microenvironment by constructing a BM-MSC-leukemia cell co-culture system. In vitro cell experiments, in vivo mouse model experiments, lentiviral transfection and transcriptome sequencing analysis were used to investigate the possible change of BM-MSCs in the leukemia niche and the potential factors in BM-MSCs that promote the progression of leukemia.In the leukemia niche, the leukemia cells reduced the MSCs' capacity to differentiate towards adipogenic and osteogenic subtypes, which also promoted the senescence and cell cycle arrest of the MSCs. Meanwhile, compared to the mono-cultured MSCs, the gene expression profiles of MSCs in the leukemia niche changed significantly. These differential genes were enriched for cell cycle, cell differentiation, DNA replication, as well as some tumor-promoting biofunctions including protein phosphorylation, cell migration and angiogenesis. Further, interferon alpha-inducible protein 6 (IFI6), as a gene activated by interferon, was highly expressed in leukemia niche MSCs. The leukemia cell multiplication was facilitated evidently by IFI6 both in vitro and in vivo. Mechanistically, IFI6 might promote leukemia cell proliferation by stimulating SDF-1/CXCR4 axis, which leads to the initiation of downstream ERK signaling pathway. As suggested by further RNA sequencing analysis, the high IFI6 level in MSCs somewhat influenced the gene expression profile and biological functions of leukemia cells.BM-MSCs in the leukemia niche have varying degrees of changes in biological characteristics and gene expression profiles. Overexpression of IFI6 in BM-MSCs could be a key factor in promoting the proliferation of B-ALL cells, and this effect might be exerted through the SDF-1/CXCR4/ERK signal stimulation. Targeting IFI6 or related signaling pathways might be an important measure to reduce the leukemia cell proliferation.© 2023. BioMed Central Ltd., part of Springer Nature.