Expression of Tie-2 and other receptors for endothelial growth factors in acute myeloid leukemias is associated with monocytic features of leukemic blasts.
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.
Riccioni
Roberta
R
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, Italy.
Diverio
Daniela
D
Mariani
Gualtiero
G
Buffolino
Sonia
S
Riti
Viviana
V
Saulle
Ernestina
E
Petrucci
Eleonora
E
Cedrone
Michele
M
Lo-Coco
Francesco
F
Foà
Robin
R
Peschle
Cesare
C
Testa
Ugo
U
D000208:Acute Disease; D042683:Angiopoietin-1 / Q000378:metabolism / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival; D042783:Endothelial Cells / Q000166:cytology; D016228:Endothelial Growth Factors / Q000378:metabolism*; D042381:Granulocyte Precursor Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016130:Immunophenotyping; D007951:Leukemia, Myeloid / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D007958:Leukocyte Count; D009000:Monocytes / Q000378:metabolism*; D009154:Mutation; D042787:Receptor, TIE-2 / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism
C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D016228:Endothelial Growth Factors; D042461:Vascular Endothelial Growth Factor A; C497970:FLT3 protein, human; D042787:Receptor, TIE-2; D040262:Receptors, Vascular Endothelial Growth Factor; D051941:fms-Like Tyrosine Kinase 3