T-ALL: several homes rather than homeless?

M icroenvironment-targeted therapies are emerging as possible complementary approaches to treat malignancies. However, progress is hindered by the complexity of the interactions between malignant cells and their microenvironment. In leukemia, this complexity is further emphasized by a highly dynamic behavior of leukemic cells recently reported in Nature. Hawkins et al. 1 analyze leukemic cell localization relative to microenvironmental cells in T-cell acute lymphoblastic leukemia (TALL) through real-time intravital imaging. Contrasting previous studies, Lo Celso and colleagues report a highly motile behavior and lack of stable interactions with specific micro-environmental cell types during disease progression or after chemotherapy. This study challenges some current concepts on microenvironmental dependence of leukemia. Leukemic cells migrate throughout the body, then identify and seed suitable territories where they can expand. Cumulative evidence suggests that the support of the bone marrow (BM) microenvironment is required for leukemia initiation, progression or resistance to therapy. In some cases, leukemic cells compete with their normal counterparts for the most permissive/ supportive areas, as similar microenviron-mental requirements have been proposed for normal hematopoietic stem cells (HSCs) and leukemia-initiating cells. 2 In a previous study, Lo Celso et al. 3 developed powerful intravital microscopy methods, which revealed that normal HSCs transplanted into irradiated mice (to promote BM homing) steadily locate near bone-forming cells (osteoblasts). 3 Osteoblasts also promote T-cell development by providing the Notch ligand DLL4. 4 In nonirradiated mice, HSCs have been preferentially found near their niche cells, such as endothelial cells 5 and their associated BM mesenchymal stem cells (BMSCs). 6 Hawkins et al. 1 take these notions further and use their optimized intravital microscopy to study leukemia, and particularly the spatial relationships of TALL cells with osteoblasts, nestin-GFP + cells (marking BMSCs) 6 and endothelial cells. Briefly, the position of transplanted TALL cells relative to osteoblasts, nestin-GFP + cells and endothelium was recorded during 3 hour imaging sessions. Different time points after transplantation reflected various stages of leukemia development. A time-lapse study was performed after the treatment with conventional chemotherapy to study the localization, division and migratory behavior of chemoresistant TALL cells. This is an impressive effort that has provided the first extensive analysis of real-time leukemic cell positioning and migration within BM niches. A major novel finding is that TALL cells (either before or after chemotherapy) seem to be highly motile and lack any apparent localization preference within BM (Figure 1). The authors envision that targeting the interactions …