Bone Marrow Microenvironment in the Pathogenesis of AML

Abstract

Acute myeloid leukemia (AML) arises from a series of genetic abnormalities in a stem or progenitor cell that lead to uncontrolled growth. Data from the past few decades have implicated the hematopoietic microenvironment (HM) in the pathogenesis of hematologic malignancies (Ramakrishnan et al., 2009). Hematopoietic stem cells (HSCs) live in a highly specialized complex microenvironment, also known as a niche (Scadden et al., 2007; Konopleva et al., 2009). Two distinct microenvironmental niches defined: “osteoblastic (endosteal)” and “vascular” niches (Perry and Li, 2007). Recent studies suggest that these niches work together. Coordination between the osteoblastic and vascular niches regulates HSC selfrenewal, proliferation, differentiation and mobilization in and out of the bone marrow (BM). HSCs leave the osteoblastic niche, mobilize to the vascular niche, and enter the blood vessel. They subsequently may undergo transendothelial migration from the peripheral circulation and return first to the vascular niche and then to the osteoblastic niche (Lapidot et al., 2005; Cancelas and Williams, 2006). Within the niche, there are critical bidirectional signals that ensure the regulation of normal HSCs (Calvi et al., 2003) and maintenance of the quiescent long-term HSC pool (Fleming et al., 2008). The quiescent fraction of immunophenotypically defined HSCs has been previously demonstrated to correlate with long-term repopulating ability of BM (Passegue et al., 2005) and loss of this fraction is associated with inability to sustain serial transplantation, the most stringent in vivo assay of self-renewal (Fleming et al., 2008). The HM consists of a complex structure of both non-hematopoietic and hematopoietic cells, extracellular matrix as well as soluble and membrane bound factors that cooperate to support normal hematopoiesis. It was known as early as the 1960s, based on experiments on mice, that normal hematopoiesis could not occur without a supportive environment (Russell et al., 1979). In vitro studies of the HM over the last several decades have mostly relied on the long-term marrow culture system, first reported by Dexter (1977). The key component of the HM is mesenchymal stromal cells (MSC). These plastic-adherent cells currently described as mesenchymal stem cells are termed multipotent mesenchymal stromal cells, while the term mesenchymal stem cell should be reserved for a subset of these cells that demonstrate stem cell activity by clearly stated criteria (Horowitz et al., 2005). MSCs are primitive cells originating from the mesodermal germ layer and were classically described to give rise to connective tissues, skeletal muscle cells, and cells of the vascular system. Friedenstein and colleagues (1974) first described MSC as fibroblast-like cells that