Acute Myeloid Leukemia and the Bone Marrow Niche-Take a Closer Look

Abstract

The bone marrow is the home of hematopoiesis and is therefore a hotspot for the development of hematopoietic diseases. Complex interactions between the bone marrow microenvironment and hematopoietic stem cells must find a balance between proliferation, differentiation and homeostasis of the stem cell compartment. Changes in this tightly regulated network can provoke malignant transformation, leading to hematopoietic diseases. Here we focus on acute myeloid leukemia (AML), since this is the most frequent acute leukemia in adulthood with very poor overall survival rates and where relapse after chemotherapy continues to be a major challenge, driving demand for new therapeutic strategies. Current research is focusing on the identification of specific interactions between leukemic blasts and their niche components, which may be exploited as novel treatment targets along with induction chemotherapy. Significant progress has been gained over the last few years in the field of high-resolution imaging. Confocal ex vivo and intravital microscopy have revealed a detailed map of bone marrow structures and components; as well as identifying numerous alterations in the stem cell niche that correspond to disease progression. However, the underlying mechanisms are still not completely understood and due to the complexity, their elucidation remains a challenging. This review discusses the constitution of the AML niche in the bone marrow, the improvement in visualization of the complex three-dimensional niche structures and points out new therapeutic strategies to increase the overall survival of AML patients.

Keywords: 3D confocal microscopy; AML; acute myeloid leukemia; angiogenesis; bone marrow; endothelial cell; niche; vasculature.

Figure 1

Leukemic blast interactions with the perivascular niche. Secreted factors and cell-cell interactions regulate the survival, proliferation and resistance of AML cells in the perivascular niche. All of them are under clinical investigation for targeted therapy. Future studies will identify further relevant pathways of the interplay between AML and its niche cells (marked with question mark). AML, acute myeloid leukemia; EC, endothelial cell; MSC, mesenchymal stromal cell; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor, CXCL12, C-X-C motif chemokine 12; CXCR4, C-X-C chemokine receptor 4; VLA-4, very late antigen 4; VCAM-1, vascular cell adhesion molecule 1.

Figure 2

3D confocal visualization of leukemic cells in the murine bone marrow. (A) Whole-mount bone preparation of fixed cryopreserved femur. (I) Bone was cleaned from tissue for fixation and cryopreservation. Next it was shaved longitudinally from both sides on a cryostat until bone marrow was fully visible (II). After optical clearing tissue appeared transparent (III). (B) Orthogonal sections of a z-stack show the relevance of 3D visualization for niche analyses. The 2D plane shows a leukemic cell (CD45, yellow) without direct contact to a sinusoidal blood vessel (endoglin, red). Orthogonal sections show an adjacent blood vessel below the AML cell. DAPI signals mark the bone marrow tissue (blue). (C) Corresponding 3D z-stack image of bone marrow vasculature with engrafted human AML cells. Cell from orthogonal section is marked with an arrow.