The role of bone marrow microenvironment (BMM) cells in acute myeloid leukemia (AML) progression: immune checkpoints, metabolic checkpoints, and signaling pathways

Abstract

Acute myeloid leukemia (AML) comprises a multifarious and heterogeneous array of illnesses characterized by the anomalous proliferation of myeloid cells in the bone marrow microenvironment (BMM). The BMM plays a pivotal role in promoting AML progression, angiogenesis, and metastasis. The immune checkpoints (ICs) and metabolic processes are the key players in this process. In this review, we delineate the metabolic and immune checkpoint characteristics of the AML BMM, with a focus on the roles of BMM cells e.g. tumor-associated macrophages, natural killer cells, dendritic cells, metabolic profiles and related signaling pathways. We also discuss the signaling pathways stimulated in AML cells by BMM factors that lead to AML progression. We then delve into the roles of immune checkpoints in AML angiogenesis, metastasis, and cell proliferation, including co-stimulatory and inhibitory ICs. Lastly, we discuss the potential therapeutic approaches and future directions for AML treatment, emphasizing the potential of targeting metabolic and immune checkpoints in AML BMM as prognostic and therapeutic targets. In conclusion, the modulation of these processes through the use of directed drugs opens up new promising avenues in combating AML. Thereby, a comprehensive elucidation of the significance of these AML BMM cells' metabolic and immune checkpoints and signaling pathways on leukemic cells can be undertaken in the future investigations. Additionally, these checkpoints and cells should be considered plausible multi-targeted therapies for AML in combination with other conventional treatments in AML. Video Abstract.

Keywords: Acute myeloid leukemia; Angiogenesis; Bone marrow microenvironment; Cancer metabolism; Chemoresistance; Immune checkpoint; Metabolic checkpoint.

Fig. 1

AML bone marrow microenvironment (BMM) cells’ immune checkpoints and component productions that contribute to angiogenesis, metastasis, and cell proliferation. The yellow concentric circle refers to cells component productions such as chemokines, cytokines, and growth factors. The purple concentric circle refers to immune checkpoints. TAM: tumor-associated macrophage; DC: dendritic cells; LIC: leukemia-initiating cell; MDSC: myeloid-derived suppressor cell; CAF: cancer-associated fibroblast; MSC: mesenchymal stromal cell; NK cell: natural killer cell; TNF-α: tumor necrosis factor-alpha; IL: interleukin; TGF-β: transforming growth factor-β; CCL: C–C motif chemokine ligand; CXCL: chemokine (C-X-C motif) ligand; NO: nitric oxide; SCF: stem cell factor; MMPs: matrix metalloproteinases; Ang: angiopoietin; IDO: indoleamine 2,3-dioxygenase; OPN: osteopontin; OCN: osteocalcin; VEGF: vascular endothelial growth factor; PDGF: platelet-derived growth factor; SDF: stromal cell derived factor; FGF: fibroblast growth factor; TIM-3: T-cell immunoglobulin and mucin domain-3; PD-1: Programmed Cell Death Protein 1; PD-L1: Programmed Cell Death Ligand 1; PGE2: Prostaglandin E2

Fig. 2

The metabolism of an acute myeloid leukemia cell. Metabolic reprogramming produces ATP and intermediates for the biosynthesis of amino acids, nucleotides, lipids, and redox components which required for high proliferation rate. Flexible changes in nourishing and processing BMM and leukemic cells in ecological conditions propel significant differences in the AML BMM cells resulting in these substances happening in the preexisting metabolic pathways to AML advancement. GLUTs: glucose transporters; MCTs: monocarboxylate transporters; α-KG: α-Ketoglutarate; PPP: pentose phosphate pathway

Fig. 3

The illustration indicates several pathways in AML cell: 1. CXCL-12/CXCR-4 axis initiates PI3K and ERK signaling pathways that leads to survival of AML cells through AKT and MAPK respectively. 2. Interaction of VEGFR-3 with its ligand (VEGF) starts PI3K/AKT/NO (survival), PI3K/BCL-2, Bag-1/Hsp, Ras/Raf (proliferation) and Ras/MKK (proliferation). 3. Several RTK ligands such as cytokines, growth factors, neurotropic factors, etc. interact with RTK that results in ERK/Ras (control of proliferation) ans p85/PDK1/AKT/mTOR. 4. some intracellular factors such as ROS and C-src are activated by GPCR. In the next step infiltration of these factors to cell membrane surface causes cleavage of proligands to ligand form of RTK. 5. HH ligands intract with PTCH. This interaction leads to inhibition of inhibitory activity of PTCH. When PTCH is inhibited, SMO can move toward the primary cillium and cause separation of GLI from SUFU. GLI in the nucleus promotes transcription of some target genes