Therapeutic targeting of microenvironmental interactions in leukemia: mechanisms and approaches

Abstract

In hematological malignancies, there are dynamic interactions between leukemic cells and cells of the bone marrow microenvironment. Specific niches within the bone marrow microenvironment provide a sanctuary for subpopulations of leukemic cells to evade chemotherapy-induced death and allow acquisition of a drug-resistant phenotype. This review focuses on molecular and cellular biology of the normal hematopoietic stem cell and the leukemia stem cell niche, and of the molecular pathways critical for microenvironment/leukemia interactions. The key emerging therapeutic targets include chemokine receptors (CXCR4), adhesion molecules (VLA4 and CD44), and hypoxia-related proteins HIF-1alpha and VEGF. Finally, the genetic and epigenetic abnormalities of leukemia-associated stroma will be discussed. This complex interplay provides a rationale for appropriately tailored molecular therapies targeting not only leukemic cells but also their microenvironment to ensure improved outcomes in leukemia.

Figure 1. Major components of osteoblastic and vascular niches

The BM microenvironment consists of a complex network of cells. The normal and leukemic stem cells 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 quiescent microenvironment for normal and leukemic stem cells. In the vascular niche around sunusoids, perivascular reticular cells, sinusoidal endothelial cells, and mesenchymal progenitors may facilitate transendothelial migration, homing, proliferation, and differentiation of normal and leukemic stem cells.

Figure 2. Hypoxia vs. Normoxia: therapeutic targets

The process of recruiting the normal and leukemic stem cells to the BM microenvironment may depend on endothelium-derived SDF-1α. Oxygen tension gradually declines from the vascular niche to the osteoblastic niche. Under hypoxic conditions of the osteoblastic niche, HIF1-α translocates into the cell nucleus, bind to the DNA target genes carrying a hypoxia-response element (HRE), and initiates the transcription of genes involved in angiogenesis, anaerobic glycolysis, and vasodilation. Activation of growth factors and cytokines, stimulation of SDF-1α/CXCR4 signaling and integrin ligation lead to increased HIF1-α by modulating its stability and increased translation through the PI3K/AKT/mTOR pathway.

Figure 3. Therapeutic targets in the bone marrow niche

In the BM microenvironment, a complex network of cells, ECM, and secreted molecules work in concert to regulate the normal and leukemic stem cells. Cytokine and chemokine signaling and integrin ligation can activate the PI3K/Akt pathway which regulates several downstream components that are involved in regulation of the normal and leukemic stem cells survival and proliferation. The novel therapeutic agents indicated in the Figure, which target the leukemic cells in their surrounding microenvironment, or interactions between leukemic cells and BM stromal cells, have been shown to destroy LSC without adversely affecting normal stem cell self-renewal.