Leukemia stem cells and microenvironment: biology and therapeutic targeting

Abstract

Acute myelogenous leukemia is propagated by a subpopulation of leukemia stem cells (LSCs). In this article, we review both the intrinsic and extrinsic components that are known to influence the survival of human LSCs. The intrinsic factors encompass regulators of cell cycle and prosurvival pathways (such as nuclear factor kappa B [NF-κB], AKT), pathways regulating oxidative stress, and specific molecular components promoting self-renewal. The extrinsic components are generated by the bone marrow microenvironment and include chemokine receptors (CXCR4), adhesion molecules (VLA-4 and CD44), and hypoxia-related proteins. New strategies that exploit potentially unique properties of the LSCs and their microenvironment are discussed.

Fig 1.

Mechanisms of normal and acute myelogenous leukemia stem cell interactions with the niche. The normal and leukemic stem cells (LSCs) reside in either the osteoblastic or vascular niche. In the osteoblastic niche at or near the endosteum, osteoblasts, octeoclasts, and stromal cells may provide a microenvironment for normal cells and LCSs. In the vascular niche around sinusoids, CD146⁺ mesenchymal progenitors facilitate transendothelial migration, homing, proliferation, and differentiation of normal cells and LSCs. Oxygen tension gradually declines from the vascular niche to the osteoblastic niche, and LSC proliferation results in expansion of hypoxic microenvironmental niches. MSC, mesenchymal stem or stromal cell.

Fig 2.

Regulators of leukemic stem cell (LSC) niche interactions in microenvironmental niches. Within bone marrow niches, a complex interplay of cells, extracellular matrix components, and secreted factors may modulate the biology of LSCs. Osteoblasts provide a source of osteopontin and stromal cell–derived factor-1 alpha (SDF-1α), which may induce migration of CXCR4-expressing LSCs toward the osteoblastic niche. Similarly, mesenchymal stem cells (MSCs) also secrete SDF-1α, as well as cytokines, which induce cell proliferation, activate prosurvival signaling cascades, and modulate the expression of the antiapoptotic molecules, potentially resulting in drug resistance. In addition, activation of the self-renewal pathways (such as Wnt) has been postulated to result in enhanced LSC survival and may, in part, be mediated through the niche. bFGF, basic fibroblast growth factor; IGF, insulin-like growth factor; IL-6, interleukin-6; VEGF, vascular endothelial growth factor; LRP, leukocyte common antigen-related phosphatase.

Fig 3.

Therapeutic targeting leukemic stem cell (LSC) niche interactions. Cytokines, chemokines, and the extracellular matrix activate the prosurvival signaling pathways (phosphatidylinositol-3 kinase [PI3K]/Akt, mitogen-activated protein kinase [MAPK], signal transducer and activator of transcription 3 [STAT3], and nuclear factor kappa B [NF-κB]) that regulate downstream components likely promoting survival and proliferation of LSCs. The therapeutic strategies designed to target the LSC within their surrounding microenvironment include adhesion molecule and cytokine antagonists as well as inhibitors of intracellular prosurvival and self-renewal pathways. These approaches may more selectively eradicate LSCs without adversely affecting normal stem-cell self-renewal. HA, hyaluronic acid; SDF-1, stromal cell–derived factor 1; PTEN, phosphatase and tensin homolog; ILK, integrin-linked kinase; HIF-1α, hypoxia-inducible transcription factor-1 alpha; GSK3, glycogen synthase kinase 3; LRP, leukocyte common antigen-related phosphatase; Bcl-2, B-cell lymphoma 2; Mcl-1, myeloid cell leukemia-1.