Leukemia stem cell-bone marrow microenvironment interplay in acute myeloid leukemia development

Abstract

Despite the advances in intensive chemotherapy regimens and targeted therapies, overall survival (OS) of acute myeloid leukemia (AML) remains unfavorable due to inevitable chemotherapy resistance and high relapse rate, which mainly caused by the persistence existence of leukemia stem cells (LSCs). Bone marrow microenvironment (BMM), the home of hematopoiesis, has been considered to play a crucial role in both hematopoiesis and leukemogenesis. When interrupted by the AML cells, a malignant BMM formed and thus provided a refuge for LSCs and protecting them from the cytotoxic effects of chemotherapy. In this review, we summarized the alterations in the bidirectional interplay between hematopoietic cells and BMM in the normal/AML hematopoietic environment, and pointed out the key role of these alterations in pathogenesis and chemotherapy resistance of AML. Finally, we focused on the current potential BMM-targeted strategies together with future prospects and challenges. Accordingly, while further research is necessary to elucidate the underlying mechanisms behind LSC–BMM interaction, targeting the interaction is perceived as a potential therapeutic strategy to eradicate LSCs and ultimately improve the outcome of AML.

The Hippo signaling pathway in leukemia: function, interaction, and carcinogenesis

“…The stimulation of Wnt signaling is a frequent, varied feature of all leukemia types. For example, individuals with FLT3-mutated AML have high amounts of β-catenin, promoting in vivo leukemia growth in xenograft mice reconstituted AML cell lines with del(5q) [ 56 ]. Furthermore, abnormal expression of Wnt pathway components such as WNT1, WNT2b, and LEF-1 is found in many AML cases, so Wnt signaling has a predictive value in AML [ 57 ].…”

Tumor Microenvironment in Acute Myeloid Leukemia: Adjusting Niches

“…Another important component of the bone marrow niches are stromal cells, which to a large extent comprise the adipose tissue, a longtime neglected component ( 12 ). Many authors distinguish a perivascular and an endosteal niche ( 10 ). It is still a matter of debate whether this distinction really can be made, since there is cumulating evidence in the support of the existence only of the former ( 13 ).…”

“…So the focus of this review is the TME of myeloid tumors, particularly AML, from the viewpoint of histopathology that may mechanistically explain how AML blasts interact with the TME to support growth and survival. For a detailed view on therapeutic approaches targeting the TME in AML, we refer to other excellent reviews focusing on that topic ( 9 , 10 ).…”

Properties of Leukemic Stem Cells in Regulating Drug Resistance in Acute and Chronic Myeloid Leukemias

“…Surrounded by a constellation of extracellular matrix (ECM) components, the majority of LSCs can generally be found in the endosteal (close to bone) and perivascular (close to sinusoids) compartments within the BM cavity [ 75 , 76 ]. LSCs engage in bidirectional crosstalk with a variety of cell types, including osteoblasts, osteoclasts, mesenchymal stromal cells, endothelial cells, neutrophils, and adipocytes in order to establish a malignant environment that supports the survival, unlimited self-renewal capacity, and quiescent nature of LSCs [ 77 , 78 , 79 ].…”