Advances in understanding the leukaemia microenvironment

Abstract

Dynamic interactions between leukaemic cells and cells of the bone marrow are a feature of haematological malignancies. Two distinct microenvironmental niches in the bone marrow, the 'osteoblastic (endosteal)' and 'vascular' niches, provide a sanctuary for subpopulations of leukaemic cells to evade chemotherapy-induced death and allow acquisition of drug resistance. Key components of the bone marrow microenvironment as a home for normal haematopoietic stem cells and the leukaemia stem cell niches, and the molecular pathways critical for microenvironment/leukaemia interactions via cytokines, chemokines and adhesion molecules as well as hypoxic conditions, are described in this review. Finally, the genetic abnormalities of leukaemia-associated stroma are discussed. Further understanding of the contribution of the bone marrow niche to the process of leukaemogenesis may provide new targets that allow destruction of leukaemia stem cells without adversely affecting normal stem cell self-renewal.

Keywords: bone marrow microenvironment; leukaemia; stem cell niche.

Figure 1. Key components of the leukemic bone marrow microenvironment

Components of normal HSC niches consist of multiple cell types including osteoblasts, Cxcl12-abundant reticular (CAR) cells, nestin-positive mesenchymal stem cells (MSCs), Lepr-expressing perivascular cells, endothelial cells and Schwann cells wrapping sympathetic nerve fibers. LSCs hijack HSC marrow spaces including perivascular and endosteal niches. The BM stromal cells and osteoblasts produce complex extracellular matrix (ECM) such as vascular cell–adhesion molecule-1 (VCAM-1), fibronectin and hyaluronic acid, which facilitate engraftment and adhesion of LSCs. Osteoblasts within endosteal niches generate transforming growth factor-β (TGF-β), angiopoietin-1 (Ang-1) and Jagged-1 (Jag-1) that in turn promote leukemia cells dormancy and decrease their chemosensitivity. CAR cells, nestin-positive MSCs, Leptin receptor-positive perivascular cells, and endothelial cells may play role for leukemia cells migration to perivascular microenvironment via cytokines, chemokines, and adhesion molecules. Inhibition of leukemia / stroma interactions causes increased leukemia cells cycling and homing to perivascular niches which can potentially be used for chemosensitization to target domant LSCs.