Bone marrow niche-mediated survival of leukemia stem cells in acute myeloid leukemia: Yin and Yang

Abstract

Acute myeloid leukemia (AML) is characterized by the accumulation of circulating immature blasts that exhibit uncontrolled growth, lack the ability to undergo normal differentiation, and have decreased sensitivity to apoptosis. Accumulating evidence shows the bone marrow (BM) niche is critical to the maintenance and retention of hematopoietic stem cells (HSC), including leukemia stem cells (LSC), and an increasing number of studies have demonstrated that crosstalk between LSC and the stromal cells associated with this niche greatly influences leukemia initiation, progression, and response to therapy. Undeniably, stromal cells in the BM niche provide a sanctuary in which LSC can acquire a drug-resistant phenotype and thereby evade chemotherapy-induced death. Yin and Yang, the ancient Chinese philosophical concept, vividly portrays the intricate and dynamic interactions between LSC and the BM niche. In fact, LSC-induced microenvironmental reprogramming contributes significantly to leukemogenesis. Thus, identifying the critical signaling pathways involved in these interactions will contribute to target optimization and combinatorial drug treatment strategies to overcome acquired drug resistance and prevent relapse following therapy. In this review, we describe some of the critical signaling pathways mediating BM niche-LSC interaction, including SDF1/CXCL12, Wnt/β-catenin, VCAM/VLA-4/NF-κB, CD44, and hypoxia as a newly-recognized physical determinant of resistance, and outline therapeutic strategies for overcoming these resistance factors.

Keywords: Bone marrow niche; Yin and Yang; acute myeloid leukemia; leukemia stem cell.

Figure1

HSCs and LSCs in bone marrow niche. Normal HSCs and LSCs reside in a BM niche created by MSC and endothelial cells that is perivascular and located in trabecular bone adjacent to sinusoids. The endothelial sinusoid is surrounded by nestin and/or leptin receptors positive MSC with high expression of the chemokine CXCL12, which is a chemoattractant for CXCR4-expressing HSCs. CD146 mesenchymal progenitors facilitate transendothelial migration, homing, proliferation, and differentiation of normal HSCs and LSCs. Bone marrow niche is hypoxic regulated by HIF-1 and HIF-2. LSC proliferation results in expansion of hypoxic microenvironmental niches.

Figure2

Crosstalk between leukemia cell and BM MSCs. LSC/leukemia cells remain dependent on signals from the BM niche for survival, proliferation, and as a sanctuary for resistance to chemotherapeutic agents. LSC engraftment and proliferation in BM induced the stromal microenvironment to create a malignant niche. Leukemic cell-induced pro-survival, growth-stimulatory signals change in MSC that mimic an inflammatory response, and potentially contribute to LSC therapy resistance. Gene set enrichment analysis (GSEA) identified activation of NF-кB as a potential cause of pro-inflammatory signaling pathway changes induced by leukemia cells in MSC.

Figure3

Experimental workflow of leukemia-BM-MSC co-culture experiments

Figure4

Therapeutic targets in BM niche. Cytokines, chemokines, and the extracellular matrix activate the pro-survival signaling pathways, such as PI3K/Akt, MAPK, STAT3, and NF-кB, which regulate downstream components likely promoting survival and proliferation of LSCs. The therapeutic strategies designed to overcome stroma-mediated chemoresistance and target the LSC include adhesion molecule and cytokine antagonists as well as inhibitors of intracellular pro-survival and self-renewal pathways.