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Osteogenic niche in the regulation of normal hematopoiesis and leukemogenesis
Phuong M. Le,1 Michael Andreeff2 and Venkata Lokesh Battula2,3
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; 2Section of Molecular Hematology and Therapy, Leukemia Department, The University of Texas MD Anderson Cancer Center, Houston, TX and and 3Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
ABSTRACT
The bone marrow microenvironment, also known as the bone mar- row 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 pro- genitor 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 progen- itor 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.
Introduction
Hematopoietic stem cells (HSCs) home to specific microenvironments in the bone marrow (BM) and receive signals that drive their fate under both normal and pathological conditions. So far, two predominant niches that differentially regu- late HSCs through their non-hematopoietic compartments and levels of hypoxia have been identified.1,2 The endosteal niche near the inner bone surface is popu- lated by osteoblastic lineage cells, including osteoprogenitor cells, pre-osteoblasts, mature osteoblasts, and osteocytes, as well as mesenchymal stromal cells (MSCs) and osteoclasts, whereas the non-endosteal niche consists mainly of sinusoidal endothelial cells, pericytes, and non-myelinating Schwann cells. Both niches are highly vascularized yet associated with distinct subtypes of blood vessels that support either the bone-forming or sinusoidal domain.3 Recent work from the Adams group also revealed a strong association between the osteogenic niche and a third vessel type that made up the transition zone in the developing bone. This subset seems to function upstream of both endosteal and sinusoidal endothelium, though more functionally related to the former, and connect the two vasculatures during the early stages of specialization.4 Stromal cells in both niches share over- lapping signatures; however, it has been suggested that endosteal MSCs support HSC quiescence whereas non-endosteal MSCs promote HSC proliferation.5
Acute myeloid leukemia (AML) is one of the most aggressive hematologic malignancies, characterized by increased numbers of myeloid precursors in the BM that fail to differentiate into more mature myeloid cells. Recent studies have
Ferrata Storti Foundation
Haematologica 2018 Volume 103(12):1945-1955
Correspondence:
vbattula@mdanderson.org
Received: May 2, 2018. Accepted: September 10, 2018. Pre-published: October 18, 2018.
doi:10.3324/haematol.2018.197004
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/12/1945
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