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

Abstract

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 in patients (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 in patients 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,) 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.

The pretransplant systemic metabolic profile reflects a risk of acute graft versus host disease after allogeneic stem cell transplantation

“…Firstly, the risk of serious complications early after allotransplantation is associated with the preconditioning serum profile of immunoregulatory and angioregulatory mediators, and the same seems to be true for systemic levels of endothelial cell-derived adhesion molecules (Lindås et al 2014; Reikvam et al 2012a). Secondly, an association between serum levels of angioregulatory Angiopoietin-2/Tie2 and relapse-free survival was described for a selected group of high-risk patients with only 17 out of 90 patients being in complete remission prior to transplantation (Koenecke et al 2010; Kümpers et al 2008). These patients are thus not comparable to our unselected patients.…”

Serum Tie2 levels: clinical association with microangiopathies in patients with systemic sclerosis

“…Given that VEGF is a potent pro‐angiogenic factor, VEGF‐mediated shedding of Tie2 appears to promote the switching from vascular quiescence to angiogenesis through the disruption of pre‐existing transassociation of Tie2 at EC–EC contacts and sTie2‐dependent modulation of Ang/Tie2 signalling. Importantly, serum sTie2 levels are elevated in patients with malignancies, 7–9 cardiovascular diseases, 10–12 and inflammatory bowel diseases, 13 suggesting that sTie2‐dependent modulation of endothelial behaviour is involved in the pathophysiology of these diseases. As VEGF levels are increased in the skin and sera of SSc patients, 14,15 sTie2 may serve as a marker of endothelial activation in SSc.…”

Correlation of Tie2 in Acute Leukemia with Disease Behaviour and Lineage Selection

“…Koenecke, agreed with us but he used ELISA for detection of Angiopoietin 2 and TIE2. He found that Angiopoietin 2 at 2.18 ng/mL was associated with a prognostic sensitivity of 55% and a specificity of 76% (AUC 0.64, p=0.002) and Tie2 concentration of 2.24 ng/mL was associated with a prognostic sensitivity of 69% and a specificity of 49% (AUC 0.62, p=0.01) [19].…”