Far from Health: The Bone Marrow Microenvironment in AML, A Leukemia Supportive Shelter

Abstract

Acute myeloid leukemia (AML) is the second most common leukemia among children. Although significant progress in AML therapy has been achieved, treatment failure is still associated with poor prognosis, emphasizing the need for novel, innovative therapeutic approaches. To address this major obstacle, extensive knowledge about leukemogenesis and the complex interplay between leukemic cells and their microenvironment is required. The tremendous role of this bone marrow microenvironment in providing a supportive and protective shelter for leukemic cells, leading to disease development, progression, and relapse, has been emphasized by recent research. It has been revealed that the interplay between leukemic cells and surrounding cellular as well as non-cellular components is critical in the process of leukemogenesis. In this review, we provide a comprehensive overview of recently gained knowledge about the importance of the microenvironment in AML whilst focusing on promising future therapeutic targets. In this context, we describe ongoing clinical trials and future challenges for the development of targeted therapies for AML.

A potential area of use for immune checkpoint inhibitors: Targeting bone marrow microenvironment in acute myeloid leukemia

“…The cellular elements consist of hematopoietic cells, stromal cells (fibroblasts, endothelial cells, endothelial progenitor cells, osteoblasts, osteoclasts, adipocytes) and noncellular elements consists of ECM components, autonomic nervous system and soluble factors such as cytokines (89). BMM is usually divided into two different anatomical locations as endosteal niche and perivascular niche (90); the main function of endosteal niche and perivascular niche is to aid long term storage of HSCs by providing a hypoxic environment and to support the proliferation and differentiation of HSCs by maintaining a more oxygenated environment, respectively. Based on their different functions and structural features, these niches have been divided into various subgroups; endosteal niche mainly comprise of osteolineage cells while the perivascular niche consists of different subtypes associated with endothelial and perivascular cells (91) (Figure 1).…”

“…Along with chronic myeloid leukemia (CML), the niche microenvironment of acute myeloid leukemia (AML) is well established: with the help of recent studies, significant progress has been made in understanding the impact of genetic mutations or functional alterations in the BM on leukemia. Examples include the deletion of Dicer1 in osteoprogenitors, which leads to the development of myelodysplastic syndrome (MDS) with The cellular components of the BM niches include endothelial cells, HSCs, megakaryocytes, osteoblasts, osteoclasts, adipocytes, sympathetic neurons that are related to Schwann's cells, bone macrophages and reticular cells (90,92). Both soluble factors and direct contact between cells regulate HSC maintenance.…”

Pediatric Acute Myeloid Leukemia—Past, Present, and Future

“…In particular, the combination with immunomodulatory agents that optimize cellular treatments shows promising efficacy in preclinical and initial clinical studies. Directly related to these approaches are the current research findings on the importance of the microenvironment [96], its interaction with leukemic blasts, and the effects it induces on the selective proliferation of malignant cells, support of escape mechanism of leukemic stem cells, and inhibition of immunocompetence of effector cells, such as T/NK cells [97].…”

Y‐box binding protein 1 in small extracellular vesicles reduces mesenchymal stem cell differentiation to osteoblasts—implications for acute myeloid leukaemia

“…Acute myeloid leukaemia (AML) is the most aggressive leukaemia characterized by chromosomal rearrangements and gene mutations in which bone marrow makes a multitude of abnormal blood cells called AML blasts or myeloblasts (Huang et al., 2020 ; Rubnitz et al., 2010 ). For years, it has been known that there is a crosstalk between AML blasts and critical components in the bone marrow microenvironment (BMM), resulting in abnormal proliferation and differentiation blockage of stem cells, which disrupts the normal haematopoiesis leading to bone marrow failure and eventually death, if left untreated (Goulard et al., 2018 ; Sendker et al., 2021 ; Yao et al., 2021 ). BMM is a complex niche that contains various cell populations, including endothelial cells, hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), fibroblasts, osteoblasts, adipocytes and many immune cells (Duarte et al., 2018 ; Hughes et al., 2022 ).…”