AML arises in hematopoietic cells residing in a bone marrow microenvironment known as the niche, where interactions with nonmalignant cells play an important role in leukemia initiation, progression, and response to therapy. Niche cells include endothelial cells, fibroblasts, adipocytes, osteoblasts, osteocytes, mesenchymal stem cells, neurons, and other cell types. There appears to be a reciprocal relationship whereby niche cells can provide signals that promote the development of hematologic malignancies and, conversely, emerging malignant clones can remodel and reprogram niche cells to favor disease progression. Many of the mechanisms that have been implicated derive from observations in animal models and have not been validated in patients. The role of the niche in normal and malignant hematopoiesis is discussed in detail elsewhere.
A hallmark of the AML niche is the production of an “inflamed” or proinflammatory microenvironment. This is characterized by aberrant expression of cytokines (e.g., interleukin [IL]-1b, tumor necrosis factor [TNF], IL-6), chemokines (CCL3, CXCL12), and alarmins. These signals are generally growth suppressive for normal hematopoiesis. Leukemic cells are able to evade this hostile microenvironment through poorly understood mechanisms to gain a relative growth advantage. Interactions with niche cells induce prosurvival factors in AML cells (e.g., BCL2, BCLXL, MCL1) through direct cell contact and soluble mediators (e.g., growth arrest specific 6 [GAS6]). Finally, the niche elaborates factors that create an immune-suppressive micro environment (e.g., indoleamine 2,3-dioxygenase [IDO], arginase) that may facilitate immune evasion by AML cells.
Although it is clear that interactions between leukemic precursors and the bone marrow niche are necessary for leukemogenesis, it is less clear which interaction is most amenable to therapeutic intervention. Early candidates include targeting the interactions between leukemic blasts and existing immune-mediators in the marrow such as T-cell or NK-cell populations, which may be amenable to immunotherapy strategies. Similarly, drug delivery to the niche may concentrate an anti leukemic effect; liposomal packaging of chemotherapeutics is based, in part, on this concept. Other strategies have sought to evaluate whether leukemic cells may be more sensitive to chemotherapy if mobilized out of the niche, including inhibiting CXCR4 or mobilizing leukemic blasts with growth factors in combination with chemotherapy.
