Yu, Kunlin, Yin, Yi, Ma, Dan, Lu, Tingting, Wei, Danna, Xiong, Jie, Zhou, Zheng, Zhang, Tianzhuo, Zhang, Siyu, Fang, Qin, and Wang, Jishi
• In this work, we firstly found the Shp2 expression in BMSCs was higher in B-ALL patients than in normal donors, especially in relapsed B-ALL patients. • We firstly found Shp2 activation in bone marrow microenvironment upregulated PI3K/AKT phosphorylation to increase VCAM-1 expression. • Shp2 activation in bone marrow microenvironment induced VCR resistance in CCRF-SB cells via VCAM-1/VLA-1 signaling between BMSCs and leukemia cells. • These provided a basis for the study on the effect of Shp2 activity on leukemia cells in the BM microenvironment. B-cell acute lymphoblastic leukemia (B-ALL) is immune to the chemotherapy-induced apoptosis as a result of the protection of bone marrow mesenchymal stromal cells (BMSCs). However, the precise underlying mechanism of such protection remains unclear so far. In this experiment, protein tyrosine phosphatase 2 (Shp2), which was encoded by the PTPN11 gene, was highly expressed in BMSCs of the newly diagnosed and the recurrent B-ALL patients. The plasmid-induced (including Shp2 E76K) Shp2 activation in BMSCs (Shp2-activated BMSCs) markedly increased the BMSCs-mediated resistance of leukemia cells both in vitro and in vivo. Additionally, studies in vitro suggested that, the expression of vascular cell adhesion molecule 1 (VCAM-1) was markedly up-regulated in Shp2-activated BMSCs, and VCAM-1 expression in BMSCs of B-ALL patients was negatively correlated with Shp2 expression. Down-regulation of VCAM-1 in BMSCs using siRNA reversed the resistance of CCRF-SB cells mediated by the Shp2-activated BMSCs. As for the molecular mechanism, the PI3K/AKT pathway mediated the regulation of VCAM-1 by Shp2. Blocking the very late antigen-4 (VLA-4) by antibodies in CCRF-SB cells dramatically reversed the resistance of CCRF-SB cells mediated by the Shp2-activated BMSCs, and decreased the adhesion effects of both CCRF-SB cells and BMSCs. In conclusion, Shp2 activation in BMSCs up-regulates VCAM-1 expression through increasing the PI3K/AKT phosphorylation level, and targeting the VCAM-1/VLA-4 signaling may serve as a clinically relevant mechanism to overcome the BMSCs-mediated chemoresistance of B-ALL cells. [ABSTRACT FROM AUTHOR]