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.
Highlights
TO ACUTE MYELOID LEUKEMIALeukemia is characterized by infiltration of the hematopoietic organs by abnormally differentiated and nonfunctional hematopoietic blasts [1]
tunneling nanotubes (TNT) were first described by Polak and colleagues, showing that acute lymphoblastic leukemia cells manipulate the mesenchymal stromal cells to induce the secretion of prosurvival cytokines and chemotactic proteins, improving their capabilities for chemotherapy resistance [64]
There is an ever-growing number of targeted therapeutic strategies to treat acute myeloid leukemia, yet patient outcome remains poor and clinicians have an urgent need to receive new treatment strategies for patients. This result is likely due to the highly heterogeneous and highly polyclonal nature of AML and approaches that target specific mutations in AML cells may result in the eradication only of single subclones and therefor are inadequate to rid patients of the disease
Summary
Leukemia is characterized by infiltration of the hematopoietic organs (bone marrow, blood, spleen, and other tissues) by abnormally differentiated and nonfunctional hematopoietic blasts [1]. High and uncontrolled proliferation of leukemic cells causes the expulsion of the normal hematopoietic system and the loss of their functions, leading to life-threatening symptoms such as thrombocytopenia, anemia, and immunodeficiency. The clinical presentation of the disease is quite uniform, the genetic and cytogenetic landscape of leukemia’s is very heterogeneous [1,2,3]. Proximal causes of leukemic development can be categorized in three major groups: [1] gene mutations and translocations, including epigenetic dysregulation, [2] immune dysregulation, and [3] changes in the bone marrow microenvironment
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