Osteogenic niche in the regulation of normal hematopoiesis and leukemogenesis

Abstract

The bone marrow microenvironment, also known as the bone marrow niche, is a complex network of cell types and acellular factors that supports normal hematopoiesis. For many years, leukemia was believed to be caused by a series of genetic hits to hematopoietic stem and progenitor cells, which transform them to preleukemic, and eventually to leukemic, cells. Recent discoveries suggest that genetic alterations in bone marrow niche cells, particularly in osteogenic cells, may also cause myeloid leukemia in mouse models. The osteogenic niche, which consists of osteoprogenitors, preosteoblasts, mature osteoblasts, osteocytes and osteoclasts, has been shown to play a critical role in the maintenance and expansion of hematopoietic stem and progenitor cells as well as in their oncogenic transformation into leukemia stem/initiating cells. We have recently shown that acute myeloid leukemia cells induce osteogenic differentiation in mesenchymal stromal cells to gain a growth advantage. In this review, we discuss the role of the osteogenic niche in the maintenance of hematopoietic stem and progenitor cells, as well as in their transformation into leukemia cells. We also discuss the signaling pathways that regulate osteogenic niche-hematopoietic stem and progenitor cells or osteogenic niche-leukemic stem/initiating cell interactions in the bone marrow, together with novel approaches for therapeutically targeting these interactions.

Figure 1.

Osteogenic niche in hematopoietic stem cell (HSC) maintenance and leukemogenesis. Interactions between HSCs and osteogenic niche cells could happen in two ways. First, HSCs stay quiescent and self-renew when they are in osteogenic niche. When they acquire mutations under physiological stress, HSCs become pre-leukemic and eventually transform into leukemia blast cells. Alternatively, genetic abnormalities in osteogenic cells in the bone marrow could induce myeloid leukemia in non-mutated or in pre-leukemic HSCs. Second, leukemic cells could induce osteogenic differentiation in mesenchymal stromal cells (MSCs), which normally go through a series of differentiation steps to become fully mature osteoblasts or osteocytes. This feedback loop, involving bone remodeling, probably fuels leukemia progression. However, the extent to which acute myeloid leukemia (AML) cells induce osteogenic differentiation is not clear. BMP: bone morphogenetic protein; CHIP: clonal hematopoiesis of indeterminate potential; CTGF: connective tissue growth factor; HSC: hematopoietic stem cell; LC: AML cell; OPN: osteopontin.

Figure 2.

Schematic representation of normal versus acute myeloid leukemia (AML)-bone marrow (BM) microenvironment. Normal BM consists of osteoprogenitor cells, pre-osteoblasts, mature osteoblasts, and osteocytes, mesenchymal stromal cells (MSCs) and osteoclasts at endosteal niche and endothelial cells, pericytes, and non-myelinating Schwann cell at non-endosteal niche. In addition to these cell types, adipocytes are present throughout the BM cavity. Hematopoietic stem cells (HSC) are present in both niche areas and gain support from stromal cells to stay quiescent and self-renew, whereas in AML BM, leukemic blasts displace HSCs from the protective niche area and occupy this sanctuary, thereby affecting normal hematopoiesis. In addition, AML cells create or expand the existing niche by inducing osteogenic but inhibiting adipogenic differentiation in MSCs. However, there are no reports suggesting higher bone volume in AML patients. Therefore, it is possible that induction of osteogenic differentiation is halted at the osteoprogenitor or pre-osteoblastic stage.

Figure 3.

Key signaling pathways in the osteogenic niche that regulate the fate of hematopoietic stem cells (HSC) and leukemia stem/initiating cells (LSCs). HSCs home to bone marrow (BM) and receive maintenance signals from both endosteal and non-endosteal niches. Various cell types in the perisinusoid region, such as CXCL12-abundant reticular (CAR) cells and endothelial cells, maintain less quiescent HSCs via CXCL12 and stem cell factor (SCF). Non-myelinating Schwann cells and osteolineage cells, including mesenchymal stromal cells (MSCs), osteoprogenitors, and premature and mature osteoblasts, play a major role in retaining slow-cycling HSCs near the bone surface. LSCs exploit the same cues from the osteogenic niche to hibernate and evade chemotherapy. In acute myeloid leukemia (AML), the BM niches are relatively hypoxic, whereas, in normal BM the hypoxic regions are more restricted to HSC-residing areas. Ang-1: angiopoietin 1; CXCL12: C-X-C motif chemokine 12; CXCR4: C-X-C chemokine receptor type 4; LSC: leukemic stem/initiating cell; OPN: osteopontin; SCF: stem cell factor; TGF-β: transforming growth factor β; TPO: thrombopoietin; VCAM-1: vascular cell adhesion protein 1; VLA-4: very late antigen-4.