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Physiological IGFBP7 levels prolong IGF1R activation in acute lymphoblastic leukemia.

Insulin and insulin-like growth factors (IGFs) are mitogenic and pro-survival factors to many different cell types, including acute lymphoblastic leukemia (ALL). Circulating IGFs are bound by IGF Binding Proteins (IGFBP) that regulate their action. IGFBP7 is a IGFBP-related protein (IGFBP-RP) that in contrast to other IGFBPs/IGFBP-RPs features higher affinity for insulin than IGFs, and was shown to bind the IGF1 receptor (IGF1R) as well. The role of IGFBP7 in cancer is controversial: on some tumors it functions as an oncogene while in others as tumor suppressor. In childhood ALL, higher IGFBP7 expression levels were associated with worse prognosis. Here we show that IGFBP7 exerts mitogenic and pro-survival autocrine effects on ALL cells, that were dependent on insulin/IGF. IGFBP7 knockdown or antibody-mediated neutralization resulted in significant attenuation of ALL cell viability in vitro and leukemia progression in vivo. IGFBP7 was shown to prolong the surface retention of the IGF1R under insulin/IGF1 stimulation, resulting in sustained IGF1R, IRS, AKT, and ERK phosphorylation. Conversely, the insulin receptor (INSR) was readily internalized and dephosphorylated upon insulin stimulation, despite IGFBP7 addition. The affinity of homodimeric IGF1R for insulin is reportedly >100 times lower than for IGF1. In presence of IGFBP7, however, 25 ng/ml of insulin resulted in IGF1R activation levels equivalent to that of 5 ng/ml IGF1. In conclusion, IGFBP7 plays an oncogenic role in ALL by promoting the perdurance of IGF1R at the cell surface, prolonging insulin/IGFs stimulation. Preclinical data demonstrate that IGFBP7 is a valid target for antibody based therapeutic interventions in ALL.