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CANCER STEM CELLS

Expression of Tie-2 and Other Receptors for Endothelial Growth Factors in Acute Myeloid Leukemias Is Associated with Monocytic Features of Leukemic Blasts

^aDepartment of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy;
^bDepartment of Cellular Biotechnologies and Hematology, University La Sapienza, Rome, Italy;
^cHematology Section, Ospedale San Giovanni, Rome, Italy;
^dDepartment of Biopathology, University Tor Vergata, Rome, Italy

Key Words. Tie-2 • Angiopoietins • Vascular endothelial growth factor • Acute myeloid leukemia • Endothelial cells

Correspondence: Ugo Testa, M.D., Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. Telephone: 00390649902422; Fax: 00390649387087; e-mail: u.testa{at}iss.it

Received November 6, 2006; accepted for publication March 28, 2007.
First published online in STEM CELLS EXPRESS   April 19, 2007.



We investigated the expression of Tie-2 in primary blasts from 111 patients with acute myeloid leukemia (AML) to evaluate a possible linkage between the expression of this receptor and the immunophenotypic and biologic properties of leukemic blasts. Tie-2 was expressed at moderate and high levels in 39 and 23 of 111 AMLs, respectively. The analysis of the immunophenotype clearly showed that Tie-2 expression in AML was associated with monocytic features. Interestingly, Tie-2 expression on AML blasts was associated with concomitant expression of other receptors for endothelial growth factors, such as vascular endothelial growth factor receptor 1 (VEGF-R1), -R2, and -R3. Tie-2⁺ AMLs were characterized by high blast cell counts at diagnosis, a high frequency of Flt3 mutations, and increased Flt3 expression. The survival of Tie-2⁺ AMLs is sustained through an autocrine pattern involving Angiopoietin-1 and Tie-2, as suggested by experiments showing induction of apoptosis in Tie-2⁺ AMLs by agents preventing the binding of angiopoietins to Tie-2. Finally, the in vitro growth of Tie-2⁺ AMLs in endothelial culture medium supplemented with VEGF and angiopoietins resulted in their partial endothelial differentiation. These observations suggest that Tie-2⁺ AMLs pertain to a mixed monocytic/endothelial lineage, derived from the malignant transformation of the normal counterpart represented by monocytic cells expressing endothelial markers. The autocrine angiopoietin/Tie-2 axis may represent a promising therapeutic target to improve the outcome of patients with monocytic AML.

Disclosure of potential conflicts of interest is found at the end of this article.