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JA Yunes - IGFBP7 as a therapeutic target in acute lymphoblastic leukemia
Although insulin and IGF1 were known to enhance ALL survival/proliferation in vitro for decades, their role in ALL has not been fully explored, except in T-ALL. Addition of insulin/IGFs alone has a small effect on ALL survival/proliferation. However, in association with one of the low affinity IGF binding proteins, IGFBP7, insulin/IGF have a significant effect on ALL biology both by stimulating the leukemia microenvironment and the leukemia cells itself. It is well documented that the interaction of acute lymphoblastic leukemic (ALL) cells with bone marrow (BM) stromal cells has a positive impact on leukemia cell survival and enhances ALL resistance to chemotherapy. We found that BM stromal cells stimulate ALL’s expression of IGFBP7. Diagnostic BM plasma from children with ALL had higher levels of IGFBP7 than controls. The extracellular IGFBP7 plus insulin/IGF, enhances asparagine synthetase expression and asparagine secretion by BM stromal cells, thus protecting ALL cells against one of the main drugs used in leukemia treatment: asparaginase. But besides this paracrine effect, IGFBP7 exerts also an autocrine action on ALL cells as well. ALL cells express the INSR and IGF1R receptors for insulin/IGFs. We found that IGFBP7 binds and inhibits the internalization of IGF1R, but not INSR, when in response to insulin/IGF1. This resulted in prolonging activation of IGF1R signaling and enhanced ALL survival and proliferation. Moreover, sustained activation of the IGF1R-PI3K-Akt axis concurred to GLUT1 upregulation, enhanced energy metabolism and increased glycolytic metabolism in ALL. All these findings were validated using clinical samples of B- and T-ALL. Importantly, we were able to show that IGFBP7 is targetable. We produced a monoclonal antibody against IGFBP7 and showed that IGFBP7 neutralization had a significant impact in ALL proliferation/survival in vitro and ALL progression in vivo. Mice treated with the anti-IGFBP7 antibody had a longer survival time. In conclusion, our observations reveal a hitherto unknown role for IGFBP7 in ALL biology, revealing a new candidate for drug development.
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