Expression of Angiopoietins and Their Receptor Tie2 in the Bone Marrow of Patients with Acute Myeloid Leukemia.

Abstract

Angiopoietin-1 (Ang-1) and its natural antagonist Angiopoietin-2 (Ang-2), both ligands for the receptor tyrosine kinase Tie2, are known to play an essential role in normal and pathological angiogenesis. However, the importance of angiopoietin signaling in the pathophysiology of hematologic neoplasias such as acute myeloid leukemia (AML) remains to be elucidated. We investigated the expression of Ang-1, Ang-2 and Tie2 by immunohistochemical analyses in bone marrow biopsies of 64 adult patients with newly diagnosed AML and correlated angiogenic factor expression with clinicopathological variables and long-term survival. Expression of Ang-2 was significantly increased in the bone marrow of AML patients (median [interquartile ranges]: 4.7 [3.3 – 5.7] AU [arbitrary units]) as compared with 16 control patients (1.5 [1.5 – 1.8] AU; P < 0.0001). In contrast, Ang-1 expression levels in AML patients did not differ from those found in controls. Thus, we observed a reversal of the Ang-1 and Ang-2 expression balance in the neoplastic bone marrow (Ang-2:Ang-1 ratio: 1.73) as compared with normal bone marrow (0.51; P < 0.0001). Furthermore, the angiopoietin receptor Tie2 was significantly overexpressed in leukemic blasts (3.8 [2.8 – 4.9] AU vs. 1.8 [1.6 – 2.3] AU; P < 0.0001). Patients expressing high levels of Ang-2 showed significantly longer overall survival (OS) than those with low Ang-2 levels (52.7 vs. 14.7 months; P = 0.039). The impact of Ang-2 expression on OS was especially evident in AML patients simultaneously expressing low levels of Ang-1 (P = 0.0298). Multivariate Cox regression analysis revealed karyotype and Ang-2 expression as independent prognostic factors for OS (hazard ratio [CI]: 3.06 [1.39 – 6.70] and 0.31 [0.14 – 0.69], respectively; P < 0.01). In conclusion, these data provide evidence that the alteration of angiopoietin balance in favor of Ang-2 may play a critical role in the pathophysiology of AML. Furthermore, high pre-therapeutic bone marrow Ang-2 levels indicate a favorable prognosis in polychemotherapy treated AML by a yet unknown mechanism.