The leukemic stem cell niche: current concepts and therapeutic opportunities

Abstract

The genetic events that contribute to the pathogenesis of acute myeloid leukemia are among the best characterized of all human malignancies. However, with notable exceptions such as acute promyelocytic leukemia, significant improvements in outcome based on these insights have not been forthcoming. Acute myeloid leukemia is a paradigm of cancer stem (or leukemia initiating) cells with hierarchy analogous to that seen in hematopoiesis. Normal hematopoiesis requires complex bidirectional interactions between the bone marrow microenvironment (or niche) and hematopoietic stem cells (HSCs). These interactions are critical for the maintenance of normal HSC quiescence and perturbations can influence HSC selfrenewal. Leukemia stem cells (LSCs), which also possess limitless self-renewal, may hijack these homeostatic mechanisms, take refuge within the sanctuary of the niche during chemotherapy, and consequently contribute to eventual disease relapse. We will discuss the emerging evidence supporting the importance of the bone marrow microenvironment in LSC survival and consider the physiologic interactions of HSCs and the niche that inform our understanding of microenvironment support of LSCs. Finally, we will discuss approaches for the rational development of therapies that target the microenvironment. Cell autonomous contributions to acute myeloid leukemiaAs for many cancers, acute myeloid leukemia (AML) has been extensively characterized as a cell autonomous disorder-that is, the genetic events leading to transformation of the normal hematopoietic cell are found within that cell and are both necessary and sufficient for the generation of leukemia. For example, leukemogenic fusion proteins, such as MLL-AF9 or MLL-ENL 1 that are expressed as a consequence of translocations involving chromosome t(9;11)(p22;q23) 2 or MOZ-TIF2 observed in AML with inv(8)(p11q13), 3 are present in leukemic blasts derived from patients with AML. Furthermore, introduction of these alleles into normal bone marrow cells-or even flow-sorted committed myeloid progenitors 3 -engenders AML in murine models of disease. These AML accurately recapitulate the human disease phenotype, including properties of "stem-ness" that include the ability to serially replate in methylcellulose in the absence of stroma and the ability to confer an AML phenotype that can be serially transplanted in vivo. Further support for the cell-autonomous nature of AML has been derived from model systems in which normal human CD34 ϩ hematopoietic cells can be transformed by MLL-AF9 4 in xenograft transplantation assays 5 or through conditional deletion of PTEN in hematopoietic stem and progenitor cells. 6 Each of these observations demonstrates the central importance of cell-autonomous contributions to the AML phenotype.

Understanding deregulated cellular and molecular dynamics in the haematopoietic stem cell niche to develop novel therapeutics for bone marrow fibrosis

“…It is hypothesized that myeloid malignancies such as PMF can be worsened by deregulation of the BM microenvironment 60, including MSCs and their progeny.…”

Neoplasms in the bone marrow niches: disturbance of the microecosystem

“…However, the subclonal residence of LSCs in preferential microenvironmental niches may mainly participate in therapy evasion. These findings should be further investigated in terms of the nature of related niches and mechanisms that protect surviving subclones [50,51]. One of the most relevant issues is to determine where LSCs find refuge to survive disruption caused by chemotherapy, usurpation of normal niches, or creation of LSC-specific niches.…”

“…Stem cells are considered as the unit of initiation and evolution of pre-cancerous and cancerous clones. The identification and characterization of stem cells in these tissues have been providing substantial insights into arresting oncogenesis and curing cancers by specifically targeting these stem cells and their resident microenvironments or niches [13,46,50,51]. Leukemogenesis in BM is one of the classic examples of events occurring in microecosystems.…”

Differential Regulation of CXCL5 by FGF2 in Osteoblastic and Endothelial Niche Cells Supports Hematopoietic Stem Cell Migration

“…Hematopoietic stem cell (HSC) self-renewal and differentiation are regulated by interactions with a variety of cells, including osteoblasts (OBs) and sinusoidal endothelial cells, in bone marrow (BM) [1][2][3]. Alterations of HSC niche function might induce pathological conditions, such as acute myeloid leukemia and myelodysplasia [4,5].…”