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

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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, (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.

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Acknowledgments

We thank all the doctors and nurses on our transplant unit and in the outpatient clinic for their dedicated work. We thank Julian Hellpap for excellent technical assistance.

Authorship

C.K. and P.K. had the initial idea, designed and performed the research, analyzed the results, prepared the figures, and wrote the manuscript. A.L. established the immunoassay and performed the measurements. W.V. stored and provided samples and reviewed the manuscript. E.D., S.B., J.K., M.E, and identified patients provided clinical data, participated in the design of the study, and reviewed the manuscript. G.G. and B.S. contributed cytogenetic data and reviewed the manuscript. A.G. supervised the project, participated in the design and interpretation of the study, and reviewed the manuscript.

Conflict of interest

The authors declare no competing financial interests.

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Authors and Affiliations

  1. Department of Hematology, Hemostasis, Oncology and Stem-Cell Transplantation, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

    Christian Koenecke, Elke Dammann, Stefanie Buchholz, Jürgen Krauter, Matthias Eder & Arnold Ganser

  2. Department of Nephrology, Hannover Medical School, Hannover, Germany

    Philipp Kümpers & Alexander Lukasz

  3. Institute of Virology, Hannover Medical School, Hannover, Germany

    Willem Verhagen

  4. Institute of Cellular and Molecular Pathology, Hannover Medical School, Hannover, Germany

    Gudrun Göhring & Brigitte Schlegelberger

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  1. Christian Koenecke
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Correspondence to Arnold Ganser.

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Christian Koenecke and Philipp Kümpers contributed equally to the manuscript and are both considered first authors.

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Koenecke, C., Kümpers, P., Lukasz, A. et al. Shedding of the endothelial receptor tyrosine kinase Tie2 correlates with leukemic blast burden and outcome after allogeneic hematopoietic stem cell transplantation for AML. Ann Hematol 89, 459–467 (2010). https://doi.org/10.1007/s00277-009-0869-5

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