IGFBP7 Fuels the Glycolytic Metabolism in B-Cell Precursor Acute Lymphoblastic Leukemia by Sustaining Activation of the IGF1R-Akt-GLUT1 Axis

Increased glycolytic metabolism plays an important role in B-cell precursor Acute Lymphoblastic Leukemia (BCP-ALL). We previously showed that IGFBP7 exerts mitogenic and prosuvival effects in ALL by promoting IGF1 receptor (IGF1R) permanence on the cell surface, thus prolonging Akt activation upon IGFs/insulin stimulation. Here, we show that sustained activation of the IGF1R-PI3K-Akt axis concurs with GLUT1 upregulation, which enhances energy metabolism and increases glycolytic metabolism in BCP-ALL. IGFBP7 neutralization with a monoclonal antibody or the pharmacological inhibition of the PI3K-Akt pathway was shown to abrogate this effect, restoring the physiological levels of GLUT1 on the cell surface. The metabolic effect described here may offer an additional mechanistic explanation for the strong negative impact seen in ALL cells in vitro and in vivo after the knockdown or antibody neutralization of IGFBP7, while reinforcing the notion that it is a valid target for future therapeutic interventions.

Automated summary

IGFBP7 promotes the permanence of IGF1R on the cell surface, prolonging Akt activation in the PI3K-Akt axis, which contributes to energy metabolism and glycolytic metabolism enhancement in BCP-ALL. Neutralizing IGFBP7 or inhibiting the PI3K-Akt pathway can restore the physiological levels of GLUT1 on the cell surface. This metabolic effect provides a mechanistic explanation for the negative impact of IGFBP7 knockdown or antibody neutralization on B cells in vitro and in vivo, highlighting its potential as a therapeutic target.