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.

Construction of Immune-Related Prognostic Signatures in Acute Myeloid Leukemia

“…AML patients bene t from these non-targeted cytotoxic drugs, but chemotherapy intolerance also is a big problem [17]. Besides, AML cells sheltered in the tumor microenvironment, where immune activities were dysregulated, resulting in cancer cells' self-renewal and developing drug-resistant [18,19,20,21]. Thus, early identify high-risk patients and provide them additional immune targeting therapies may have promising results in clinical management.…”

Cell interactions in the bone marrow microenvironment affecting myeloid malignancies

“…33 Notably, adipocytes have been implicated in chemoresistance by metabolizing and sequestering chemotherapeutic agents, thus protecting malignant cells. 34,35 In addition to the impaired osteogenic and adipocytic differentiation of MSCs and OLCs, AML reduces expression of key hematopoietic cytokines (CXCL12, SCF) from endothelial cells. 29 BM endothelial cells are critical components of the HSC niche and have been shown to undergo morphological and structural alterations during hematologic disease, including AML 27 and CML.…”

“…Elevated NO levels lead to increased vascular leakiness associated with therapy resistance. 35,41 Live imaging of animals with AML has also revealed striking vascular effects. 42 AML cells clustered near the endosteum and were associated with gradual loss of endosteal endothelial and osteoblastic cells, whereas central vessels were unaffected.…”

Interleukin-33 Promotes Cell Survival via P38 MAPK-mediated Interleukin-6 Gene Expression and Release in Pediatric AML

“…In AML, the most relevant microenvironment is within the bone marrow (BM) [7]. A critical role of the BM and the development of AML have been reported in different studies [8][9][10][11]. However, the relationship between cytokines in the BM and leukemia cell activity are not fully investigated.…”