Overexpression of heme oxygenase‐1 in microenvironment mediates vincristine resistance of B‐cell acute lymphoblastic leukemia by promoting vascular endothelial growth factor secretion

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.

Transcriptome Analysis Identifies LINC00152 as a Biomarker of Early Relapse and Mortality in Acute Lymphoblastic Leukemia

“…Our co-expression analysis revealed that LINC00152 regulates genes involved in substrate cellular adhesion processes, one of the main biological mechanisms associated with relapse and chemoresistance in ALL. Chemoresistance has been addressed in several studies as one of the most important mechanisms of relapse and death in ALL [40][41][42]. Taking together, these data and our findings regarding the association between LINC00152 high expression and the high risk of relapse suggest that LINC00152 could be potentially involved in chemoresistance; however, functional studies are required to prove these remarks.…”

Mechanisms of Immune Evasion in Acute Lymphoblastic Leukemia

“…This intercellular communication leads to the secretion of prosurvival cytokines (IL-8) and chemoattractants interferon gamma-induced protein/ CXC chemokine ligand 10 (IP10/CXCL10), monocyte chemotactic protein-1 (MCP-1)/CCL2) enhancing the resistance of leukemic cells to steroids [76]. In addition, via the expression of heme oxygenase-1 and the release of vascular endothelial growth factor (VEGF), MSCs promote resistance to vincristine [77]. MSCs can also protect ALL cells against the treatment by secretion of soluble or stroma-cell-bound galectin-3, which stimulates expression of endogenous LGALS3 mRNA and activates the tonic NF-κB pathway in leukemic cells [78].…”

The Complexity of the Tumor Microenvironment and Its Role in Acute Lymphoblastic Leukemia: Implications for Therapies

“…Moreover, VEGF and basic fibroblast growth factor (bFGF) were also detected in urine and peripheral blood samples from ALL patients and correlated with the increase in bone marrow angiogenesis ( 103 ). VEGF can be regulated by signaling pathways such as PI3K/AKT, as demonstrated in B-ALL cell lines and patients, where an overexpression of heme oxygenase-1 (HO-1) was found in the bone marrow stromal cells (BMSCs) ( 104 ). It was found that B-ALL cell lines became resistant to the chemotherapeutic agent vincristine (VCR) in presence of VEGF recombinant protein induced by HO-1 expression.…”