IGFBP7 participates in the reciprocal interaction between acute lymphoblastic leukemia and BM stromal cells and in leukemia resistance to asparaginase

Abstract

The interaction of acute lymphoblastic leukemia (ALL) blasts with bone marrow (BM) stromal cells (BMSCs) has a positive impact on ALL resistance to chemotherapy. We investigated the modulation of a series of putative asparaginase-resistance/ sensitivity genes in B-precursor ALL cells upon coculture with BMSCs. Coculture with stromal cells resulted in increased insulinlike growth factor (IGF)-binding protein 7 (IGFBP7) expression by ALL cells. Assays with IGFBP7 knockdown ALL and stromal cell lines, or with addition of recombinant rIGFBP7 (rIGFBP7) to the culture medium, showed that IGFBP7 acts as a positive regulator of ALL and stromal cells growth, and significantly enhances in-vitro resistance of ALL to asparaginase. In these assays, IGFBP7 function occurred mainly in an insulin-and stromal-dependent manner. ALL cells were found to contribute substantially to extracellular IGFBP7 levels in the conditioned coculture medium. Diagnostic BM plasma from children with ALL had higher levels of IGFBP7 than controls. IGFBP7, in an insulin/IGF-dependent manner, enhanced asparagine synthetase expression and asparagine secretion by BMSCs, thus providing a stromal-dependent mechanism by which IGFBP7 protects ALL cells against asparaginase in this coculture system. Importantly, higher IGFBP7 mRNA levels were associated with lower leukemia-free survival (Cox regression model, P ¼ 0.003) in precursor B-cell Ph(À) ALL patients (n ¼ 147) treated with a contemporary polychemotherapy protocol.

Adipocytes Cause Leukemia Cell Resistance to L-Asparaginase via Release of Glutamine

“…Our results complement the recent finding that bone marrow-derived mesenchymal cells (MSCs) protect leukemia from ASNase treatment through ASN secretion (19–21). Laranjeira et al showed that leukemia-cell secretion of IGFBP-7 increased ASN synthesis by stromal cells (21).…”

“…As adipose tissue is a major contributor to the whole body GLN pool (16), obesity may impair GLN depletion. Moreover, it has been proposed that non-malignant cells might support leukemia cells during ASNase treatment through local secretion of amino acids (17), an idea that has been further explored more recently (18–21). …”

Investigating chemoresistance to improve sensitivity of childhood T-cell acute lymphoblastic leukemia to parthenolide

“…The BM microenvironment can also play a role in leukemia drug resistance, mediated by a diverse set of mechanisms, both by direct cell adhesion 11,13,27 and/or soluble factor release. 12,20,28,29 In this study, the protective effects of MSC against PTL toxicity were related to decreases in ROS stress and preserved rGSH levels, suggesting that MSC increased the anti-oxidative stress capacity of T-ALL cells and thereby conferred resistance to PTL. To eliminate variability, MSC were generated from a single normal BM donor, allowing direct comparison of the effects on the patients’ samples.…”

IGFBP7 functions as a potential lymphangiogenesis inducer in non-small cell lung carcinoma

“…Furthermore, IGFBP7 plays a positive, contributing role in the interaction between leukemia cells and the microenvironment, which may promote the leukemic cell adhesion, invasion and migration (31). another assay with IGFBP7 knockdown and acute lymphoblastic leukemia (aLL), showed that IGFBP7 acts as a positive regulator of aLL and stromal cell growth, and significantly enhances in vitro resistance of aLL to sparaginase (32). Hypomethylation of IGFBP7 is likely to characterize an immature and a more malignant subtype of the disease (33).…”