BM-MSCs display altered gene expression profiles in B-cell acute lymphoblastic leukemia niches and exert pro-proliferative effects via overexpression of IFI6

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

B-cell acute lymphoblastic leukemia; Interferon alpha-inducible protein 6; Mesenchymal stem cells; Proliferation; Tumor microenvironment.