Title : Acute Lymphoblastic Leukemic cells modulate bone marrow angiogenesis : role of endothelin-1 and hypoxia ; Les cellules leucémiques de LAL modulent-elles l'angiogenèse dans la moelle osseuse ? Rôle de l'endothéline-1 et de l'hypoxie

Increased microvessel density has been described in the bone marrow of patients with Acute Lymphoblastic Leukemia (ALL). The bone marrow is an hypoxic microenvironment, and hypoxia is an important event in triggering angiogenesis. However, the crosstalk between ALL cells and endothelial cells has not been well explored, and usual in vitro assays use cells maintained under 21% O2, which did not mimic bone marrow environment. In this study, the angiogenic activity of factors secreted by the human B-ALL Nalm-6 cell line was tested by using conditioned serum-free medium, that was applied on the human bone marrow endothelial cells HBME-1. Under 21% O2, factors secreted by Nalm-6 cells induced an angiogenic response on HBME-1 cells in vitro. This angiogenic response was not dependent on VEGF secretion but involved, at least in part, the endothelin-endothelin receptor axis. The influence of hypoxia was then studied by culturing both cell lines under 5% O2, an oxygen tension that fits the bone marrow microenvironment. Hypoxia stimulated the secretion of VEGFA by both Nalm-6 and HBME-1 cells, but the angiogenic response to leukemic conditioned medium was altered by chronic hypoxia, which affects the ability of endothelial cells to respond to endothelin-1. Thus, we concluded that leukemic secretion products did not induce angiogenesis at oxygen conditions met in vivo. This work highlights the importance of the oxygen rate in the modulation of cell interactions within the bone marrow, not yet well explored in ALL.