EGFL7 Antagonizes NOTCH Signaling, Stimulates Blast Proliferation and Confers Poor Prognosis in Cytogenetically-Normal Acute Myeloid Leukemia (CN-AML)

Epidermal growth factor-like domain 7 (EGFL7) is a secreted protein and plays an important role in angiogenesis by regulating the growth, proliferation and migration of endothelial cells. Recent studies in solid tumors have shown that EGFL7 is overexpressed and is associated with a more aggressive disease phenotype. Whether EGFL7 plays a similar role in blood cancers such as acute myeloid leukemia (AML) however, has not been previously reported. To investigate the association of EGFL7 expression with outcome in AML, we measured EGFL7 mRNA expression in newly diagnosed older (≥60 years, n=126) CN-AML patients. In these patients, those with high EGFL7 expression were less likely to achieve CR (52% v 76%, P =.009). Patients with high EGFL7 expression status had shorter event-free survival (5-year rates: 6% v 13%, P =.03) and overall survival (5-year rates: 10% v 16%, P =.009) than patients with low EGFL7 expression status. To validate our clinical data we measured EGFL7 mRNA in primary AML blasts (n=11) compared to normal bone marrow (NBM) (n=5) using RT-PCR, and found a ~2.4 fold-increase in the AML samples, P Lobry C et al., (JExpMed 2013) demonstrated that although NOTCH2 and to a lesser extent, NOTCH1, mRNA was relatively abundant, NOTCH signaling was inhibited in AML blasts. Re-activation of the canonical NOTCH pathway, released a block in differentiation resulting in eradication of the leukemic blasts. Schmidt MH et al., (Nat Cell Biol. 2009) demonstrated that EGFL7 was capable of binding NOTCH receptors and blocking their subsequent activation. Therefore, we hypothesized that one mechanism by which the NOTCH pathway is kept inactive in AML is through autocrine binding of EGFL7 protein to NOTCH receptors. Co-immunoprecipitation assays confirmed binding of EGFL7 to NOTCH2 in both human primary AML cells (n=3, P HES1 and NRARP (n=3, P EGFL7 is associated with worse prognosis in patients with CN-AML, and that EGFL7 is expressed and secreted by the AML cells in an autocrine fashion, promoting their growth in part through antagonizing NOTCH2 activation. Targeting EGFL7 with antibodies to reduce NOTCH binding might represent a novel therapeutic approach to reactivate NOTCH signaling, allowing for blast differentiation and elimination of AML. Disclosures No relevant conflicts of interest to declare.