Shedding of the endothelial receptor tyrosine kinase Tie2 correlates with leukemic blast burden and outcome after allogeneic hematopoietic stem cell transplantation for AML.

Angiogenesis plays an important role in the growth and viability of hematologic malignancies. Emerging data suggest a crucial involvement of the endothelial-specific Tie2 receptor and its antagonistic ligand Angiopoietin-2 (Ang-2) in this process. The purpose of this study was to elucidate whether the soluble domain of the Tie2 receptor (sTie2)predicts outcome in patients with acute myeloid leukemia(AML) undergoing allogeneic hematopoietic stem cell transplantation(HSCT). Serum levels of sTie2 and Ang-2 were measured by ELISA in 181 AML patients before conditioning for HSCT. The median follow-up time was 22 months after HSCT. Pre-HSCT sTie2 levels were significantly higher inpatients (median 2.2 (range 1.8-3.0) ng/mL) compared to healthy controls (1.3 (0.9-1.6); p<0.0001). Elevated sTie2 levels were independently associated with active AML but did not relate to cytogenetics/mutational status before transplantation. Logistic regression analysis identified elevated sTie2 (odds ratio (OR) 3.07 (95% confidence interval(CI; 1.56-6.04), p=0.001) as a strong predictor for disease relapse and poor overall survival after HSCT. In a multimarker approach the highest risk for relapse was observed inpatients with both elevated sTie2 and elevated Ang-2 (OR 4.07, (95% CI 1.79-9.25) p<0.0001), as well as patients with both elevated Ang-2 and elevated bone marrow blast count (OR 4.16, (95% CI 1.88-7.36) p<0.0001). Elevated serum sTie2 levels were related to active leukemia,correlated with the percentage of leukemic blasts in the bone marrow, and independently predicted relapse in AML patients after allogeneic HSCT. Furthermore, our data indicate that Tie2 shedding and Ang-2 release seem to reflect overlapping, but nevertheless distinctive features in leukemia-associated neoangiogenesis.