Overexpression of heme oxygenase‐1 in microenvironment mediates vincristine resistance of B‐cell acute lymphoblastic leukemia by promoting vascular endothelial growth factor secretion. Issue 10 (2nd July 2019)

• Record Type: Journal Article
• Authors: Yu, Kunlin; Wang, Jishi; Lu, Tingting; Ma, Dan; Wei, Danna; Guo, Yongling; Cheng, Bingqin; Wang, Weili; Fang, Qin
• Is Part Of: Journal of cellular biochemistry. Volume 120:Issue 10(2019)
• Page Start: 17791
• Page End: 17810
• Publication Date: 2019-07-02
• Subjects: B‐cell acute lymphoblastic leukemia -- bone marrow stromal cell -- drug resistance -- heme oxygenase‐1 -- vascular endothelial growth factor -- vincristine; Cytochemistry -- Periodicals; 572
• DOI: 10.1002/jcb.29046
• Languages: English
• ISSNs: 0730-2312

Abstract

Abstract: Chemoresistance often causes treatment failure of B‐cell acute lymphoblastic leukemia (B‐ALL). However, the mechanism remains unclear at present. Herein, overexpression of heme oxygenase‐1 (HO‐1) was found in the bone marrow stromal cells (BMSCs) from B‐ALL patients developing resistance to vincristine (VCR), a chemotherapeutic agent. Two B‐ALL cell lines Super B15 and CCRF‐SB were cocultured with BMSCs transfected with lentivirus to regulate the expression of HO‐1. Silencing HO‐1 expression in BMSCs increased the apoptotic rates of B‐ALL cell lines induced by VCR, whereas upregulating HO‐1 expression reduced the rate. Cell cycle can be arrested in the G2/M phase by VCR. In contrast, B‐ALL cells were arrested in the G0/G1 phase due to HO‐1 overexpression in BMSCs, which avoided damage from the G2/M phase. Vascular endothelial growth factor (VEGF) in BMSCs, as a key factor in the microenvironment‐associated chemoresistance, was also positively coexpressed with HO‐1. VEGF secretion was markedly increased in BMSCs with HO‐1 upregulation but decreased in BMSCs with HO‐1 silencing. B‐ALL cell lines became resistant to VCR when cultured with VEGF recombinant protein, so VEGF secretion induced by HO‐1 expression may promote the VCR resistance of B‐ALL cells. As to the molecular mechanism, the PI3K/AKT pathway mediated regulation of VEGF by HO‐1. In conclusion, this study clarifies a mechanism by which B‐ALL is induced to resist VCR through HO‐1 overexpression in BMSCs, and provides a novel strategy for overcoming VCR resistance in clinical practice. Abstract : Overexpression of heme oxygenase‐1 (HO‐1) in bone marrow stromal cells (BMSCs) mediates B‐cell acute lymphoblastic leukemia cells resistant to vincristine which may occur via the promotion of vascular endothelial growth factor secretion in BMSCs‐conditioned medium, and HO‐1 overexpression regulated VEGF in BMSCs via activating PI3K/Akt pathways.