In normal BM, HSCs reside very near the endosteal bone surface [32]. It was found that HSCs that reside in this type of niche have a highly proliferative capacity and long-term self-renewal properties [33]. The cellular component of the endosteal niche typically involves osteoblasts (the main cells supporting myelopoiesis), osteocytes, osteoclasts and Schwann cells, and regulatory T-cells (T-regs).

The osteoblasts are the primary cells that form a connection between bone and the BM in the endosteal niche. Osteoblasts can be divided into two types: oval-shaped osteoblasts and spindle-shaped N-cadherin + osteoblasts. Both play an essential role in the regulation of hematopoiesis [34]. Additionally, they control HSC expansion and self-renewal in vivo through colony-stimulating factor 3 (CSF3) [35]. The communication between osteoblasts and HSCs in the endosteal niche can be facilitated through various mechanisms as osteoblasts produce several cytokines and growth factors that regulate HSC homing, quiescence, and mobilization.

One study has shown that an increased number of osteolineage cells, correlated with an increased number of HSCs through the action of activated parathyroid hormone receptor [35], and another one described the effect of the bone morphogenetic protein receptor type IA (BMPRIA) depletion [34]. It has been proven that osteolineages cells are essential players that control the generation of cellular elements of adaptive immune response like B and T lymphocytes [36–38].

Osteoclasts play an essential role in bone remodeling by creating resorption pits (Howship’s lacunae), they are multinucleated cells found in bone. Osteoclast progenitors originate from hematopoietic cells in BM and blood vessels that supply bone [39]. It is believed that osteoclasts are implicated in the maintenance of the endosteal niche cavities through the receptor activator of the nuclear factor kappa B ligand (RANKL) [40]. Osteoclasts have been involved in HSC mobilization as a response to stressful conditions and therapeutic agents such as CSF3 [41] through the generation of some proteolytic enzymes that cleave factors involved in the HSC niche [42]. Additionally, osteoclast depletion is associated with impairment in normal hematopoiesis and an increase in EH [43].

Mesenchymal stromal cells (MSCs) also called stromal cells are located near BM blood vessels and they are capable of self-renewal and differentiation into osteolineage cells, chondrocytes, adipocytes, and myofibres [44]. The progenitor of BM MSCs has recently been identified as skeletal stem cells (SSC) based on their differentiation capabilities [45]. MSCs are distinct from HSCs, they do not express CD45, CD34, CD41, CD14, and T- or B-cell markers [46].

MSCs expressing the intermediate filament protein nestin (nestin⁺ MSCs) enhance HSC differentiation by constitutive secretion of several hematopoietic cytokines and in response to interleukin 1 (IL1) [47]. Because of their substantial role in hematopoiesis, MSCs have been investigated in allogeneic HSC transplants [48] as they proved their ability to enhance engraftment in animal models [49]. On the contrary, the ablation of nestin⁺ MSCs in BM transplantation recipients also reduces hematopoietic stem and progenitor cells (HSPCs) homing into the BM by 90%, and they were found to be localized with Lin⁻CD48⁻CD150⁺ HSCs, pointing at their role as niche cells [41]. Additionally, the cultivated MSCs express a variety of bioactive compounds with anti-apoptotic, immunomodulatory, angiogenic, anti-scarring, and chemoattractant qualities. These findings support the use of MSCs as a potential resource to establish local regeneration environments in vivo [50].

CXCL12-abundant reticular (CAR) cells are a small number of reticular cells that are considered a subpopulation of mesenchymal cells with long processes, expressing high amounts of CXCL12 and its receptor (CXCR4) [51] play a crucial role in maintaining the pool of HSCs and their lymphoid progenitors. In fact, this proves that CAR cells are essential cellular niches for HSCs. In vivo, ablation of CAR cells results in reduced HSC cycling, increased expression of myeloid commitment markers such as PIRAT1 and CSF1R, and major loss of adipogenic and osteogenic capacity [52].

BMECs typically line the BM sinusoidal system and also make cell-to-cell contact with other cell types within the BM environment, owing to their anatomical characteristics they act as a doorkeeper and a major barrier that regulates cellular and chemical movement between the BM and the blood circulation [53]. Additionally, the BM endothelium can also influence hematopoiesis through cytokines secretion, even without cell-to-cell interaction [54].

ECs play a direct and indirect role in maintaining HSCs through an expression of the Notch ligands JAG1, JAG2, DLL1, and DLL4. They activate the Notch pathway, which helps in the self-renewal of LT-HSCs in vitro and the rebuilding of the LT-HSC pool in vivo after myeloablation [55]. Additionally, it is proven that ECs secrete various cytokines and express multiple adhesion molecules such as selectin E, selectin P, and vascular adhesion molecule 1 (VCAM1) [56], it is worth mentioning that selectin E, expressed exclusively by ECs, promoted HSC proliferation, as demonstrated by the increased HSC quiescence and self-renewal [57].

It has been proposed that fat from different tissues differs from BM fat. Bone marrow adipose tissue (BMAT) seems to be smaller in size, distributed throughout the BM, rather than having been arranged into lobules. The number of yellow marrow is increased by age and it is accompanied by a decrease in HSCs in return, studies on mice treated with adipogenic inhibitors showed an increase in HSCs engraftment, thus adipocytes act as a negative control of hematopoiesis [58]. It is claimed that the BMAT can secrete substances such as cytokines and hormones to contact with other cells in the BM environment. Additionally, BMAT exhibits different genes compared to compared to subcutaneous adipocytes [59]. Furthermore, BM adipocytes can secret leptin which may help in myelopoiesis [60].

It has been determined that sensory and autonomic innervation of the BM helps in the process of the HSC niche regulation [61]. The sympathetic nervous system (SNS) plays a substantial role in controlling the cyclical circadian release of HSCs through the effect of the secreted catecholamines on (CXCL12) by MSCs through the B3-adrenergic receptor [61]. Moreover, it was proposed that non-myelinating Schwann cells may help in HSC quiescence and hibernation through activation of TGFB (SMAD) signaling [62].

Megakaryocytes are a huge in size but scarce population of BM cells with a lobulated nucleus, they are highly specialized precursor cells that are responsible for the production and release of platelets into the circulation. Recently, several investigations have revealed that megakaryocytes play new roles in controlling the physiology and homeostasis of the BM. Recently, it has been discovered that megakaryocytes have new roles in regulating the BM’s physiology and homeostasis [63].

It has been suggested that there is a definite interaction between megakaryocytes, HSCs, and osteolineage niche within the BM, as megakaryocytes increase osteoblast proliferation after total body irradiation [64]. After BM transplantation, osteoblasts proliferate rapidly in response to mesenchymal growth factors released by megakaryocytes, such as platelet-derived growth factors. This process helps with HSC engraftment and hematopoietic reconstitution [65].

Megakaryocytes secrete various cytokines [e.g., thrombopoietin, TGFB, fibroblast growth factor 1 (FGF1), and CXCL4] through them they can help in regulating HSCs. Thrombopoietin is responsible for the migration of megakaryocytes to the endosteum and its administration to megakaryocyte-depleted mice helps restore HSCs’ quiescence state [66]. TGFB secreted by megakaryocytes maintains HSCs quiescence in the physiological state, on the other hand, under stressful conditions FGF1 promotes HSC expansion [67]. Additionally, CXCL4 secreted by the megakaryocytic pool exerts a negative control effect on HSC proliferation and decreases engraftment [68].

The BM creates a specialized immune-privileged environment that protects HSCs from any attack from the immune system by suppressing the immunological responses, which even allows foreign allografts to survive for longer periods. This protection is achieved through a complex interplay of various systems within the body [69].

The genomics revolution has enabled entire tissues, such as the hematopoietic system, to be interrogated comprehensively at single-cell resolution, revealing a valuable degree of functional and phenotypic variation within cell compartments presumed previously to be homogeneous. This heterogeneity reveals how cells decide their fate and differ in their roles in maintaining the hematopoietic niche. For instance, single-cell RNA sequencing (scRNA-seq) paves the road to identify, classify, and discover new or rare cell types and subtypes from different human organs and tissues, giving more profound information about health and disease in many fields [82]. Moreover, it allows the identification of thousands of genes in each cell, providing an unbiased characterization of their transcriptional diversity even within phenotypically homogenous populations [83].

Several landmark studies have illustrated the molecular complexity of the murine BM microenvironment based on scRNA-seq [2, 84]. In stressful conditions, some transcriptional remodeling of niche elements occurs like adipocytic skewing of perivascular cells, and downregulation of vascular Notch delta-like ligands (encoded by DLL1 and DLL4) [2]. Baccin et al. [85] performed scRNA-seq on 7,497 cells, arranged into 32 clusters corresponding to distinct cell types or stages of differentiation. They also revealed two different subsets of CAR cells: a more abundant Adipo-CAR cell population expressing adipocyte-related genes located adjacent to sinusoids and a less abundant Osteo-CAR cell population (enriched in osteolineage-related genes) located in endosteal BM regions or associated with arteriole-like vessels.

Li et al. [86] used scRNA-seq to investigate the human non-hematopoietic BME aiming to identify potential novel marrow stromal subsets and cellular hierarchies as well as to establish functional relationships between stromal and hematopoietic elements. They identified six transcriptionally and functionally different stromal cell populations and demonstrated that certain types of MSCs have the highest colony-forming units-fibroblast (CFU-F) potential and trilineage differentiation capacity with astonishing capability of interaction with all Hematopoietic cells through CXCL12 pathways. Moreover, Severe et al. [87] were able to identify 28 distinct subsets of stromal cells in BM under steady-state conditions by using single-cell mass cytometry, although only half of them expressed hematopoiesis-relevant cytokines. They emphasized that the CD73⁺ stromal subset is likely to promote HSPC engraftment and acute hematopoietic recovery following radiation conditioning.

Adhesion of LSCs to the BM niche is a crucial process in AML pathogenesis and progression. Establishing their roles and how they interplay can be a major therapeutic target in AML management. CD44 is a cell-surface glycoprotein that attaches to the extracellular matrix proteins hyaluronan, osteopontin, and selectin E. One study revealed that in comparison to normal HSCs, the expression of CD44 variant exons is more prevalent in AML cells [103] also some studies showed that high levels of CD44 molecules were essential for AML relapse in mouse models of AML [104]. Moreover, reducing surface levels of CD44 in AML cells by polymeric nanoparticles can induce apoptosis and reduce the adhesion of AML cells to mesenchymal stem cells in human BM [105]. Understanding the biology and the pathological impact of expression of CD44 in the maintenance of LSCs niche can be a potential therapeutic target for AML through the administration of anti-CD44 antibody-like in mice infected with human AML cells [103].

Selectin E, another adhesion molecule located in the BM vascular niche promotes the proliferation of normal HSC, one study, by using flowcytometry demonstrated that AML blast cells express selectin E ligands. Selectin E upregulates both the WNT and sonic hedgehog pathways in AML resulting in promoting AML blast cells survival so by targeting those molecules through the addition of GMI-1271 (uproleselan) to the AML initial therapy protocol a better outcome may be achieved [106–109].

Very late antigen 4 (VLA4), composed of α4 and β1, binds to both the CS1 domain of fibronectin (Fn) and VCAM1 and has a critical role in HSCs retaining in the BM niche. VLA4 is highly expressed AML blasts. Chemotherapy drug resistance that results from disturbance in adhesion is caused by either the activation of survival pathways or the suppression of apoptotic processes. Some examples of signal transduction pathways that may be involved include PI3KCA/AKT/BCL2, PI3K/ILK/AKT, and WNT/GSK3B/NF-κB. AS101 is an anti-VLA4 inhibitor in clinical research, it inhibits VLA4 by binding Fn and suppressing PI3K/AKT/BCL2 signaling leading to increased chemo-sensitivity in mouse xenograft of AML [110].

Cytokine signaling is crucial in maintaining BM niche homeostasis by precisely regulating cross-talks between the different cellular components. Not surprisingly, the malignant BMM mediates LSCs attachment to their niches by up-regulation of various cytokines and chemokines.

CXCL12 is one of the most crucial chemokines secreted by the MSC, in particular, CAR cells. CXCL12 is secreted in a large amount in AML. The interaction between stromal and leukemic cells is mediated by the interaction between CXCL12 and its CXCR4 receptor [111]. Notably, CD34⁺ AML leukemic blast cells have a huge amount of CXCR4 receptors on their surfaces [112] and migrate in response to CXCL12 [113]. The CXCL12/CXCR4 axis is now considered a crucial player in LSCs survivability and proliferation through the activation of proliferative and pro-survival pathways like the JAK/STAT, PI3K/AKT, and MEK/ERK pathways [112].

Several factors regulate CXCL12/CXCR4 axis in AML such as chemotherapy-induced stress and FTL3 gene mutation status [114, 115]. The expression of CXCR4 on AML blast cells could be correlated with the adhesive and migratory potential of the leukemic cells within the BM niches [116]. Moreover, the prognostic significance of the CXCL12/CXCR4 axis in leukemia has been studied to develop risk-stratified treatment approaches. Elevated CXCR4 expression in LSCs has been found to correlate with a significantly poor outcome and high recurrence rate. Additionally, CXCR4/CXCL12 can be considered an indirect mechanism that plays an important role in drug resistance. A variety of inhibitors, peptides, and antibodies have been developed to efficiently destroy, and induce apoptosis in CXCR4-expressing cancerous cells [117]. Due to these characteristics, CXCR4 inhibitors are gaining more interest as a monotherapy or as part of an ablative chemotherapeutic regimen in the context of hematopoietic cell transplantation (HCT) [118]. For example, the tolerability and safety of plerixafor have been demonstrated in patients with AML undergoing allogeneic hematopoietic stem cell transplantation (HSCT) [119], and in phase 1 trials for patients with relapsed/refractory acute leukemia [120]. Additionally, LY2510924, another potent CXCR4 peptide antagonist, led to a phase 1 study that demonstrated safety and yielded a response signal in patients with relapsed/refractory AML in combination with Idarubicin, and cytarabine [121]. Furthermore, ulocuplumab is a human IgG4 monoclonal anti-CXCR4 antibody that has therapeutic potential for several hematologic malignancies including AML [122], clinical studies have demonstrated the ability of ulocuplumab to mobilise leukemic cells into the circulation, rendering them more susceptible to chemotherapy-induced toxicity in patients with AML [123, 124].

The word “angiogenesis” comes from the Greek words “angeio” meaning blood vessel and “genesis” meaning creation. It refers to the process of forming new blood vessels. Angiogenesis enhances the growth of cancerous cells by continuously supplying them with nutrition, oxygen, and growth factors from the surrounding milieu. Various studies suggest that angiogenic factors and/or vascularization in solid tumors can be a crucial indicator for cancer treatments and have prognostic significance [125]. However, the significance of vascularization in “liquid tumors” or leukemias, which do not require the establishment of vasculature for oxygenation, is not well understood [126]. The mechanism of BM angiogenesis in hematological malignancies is more complex than that of tumor angiogenesis. The vasculature of BM is peculiar and consists of small vessels called sinusoids which have distinctive structural and functional properties that differentiate them from other malignant tissues [53].

There are several methods for evaluation of angiogenesis in AML such as measuring the serum or plasma level of circulating angiogenic factors, evaluation of cellular expression of angiogenic factors in leukemic blasts by flowcytometry [126], quantification of the number of circulating endothelial progenitor cells (cEPCs) by flow cytometry in peripheral blood [127], measuring of bone-marrow microvessel density (MVD) [128]. MVD is done by immunohistochemical analyses on BM and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) which is a noninvasive technique that quantifies global and functional BM angiogenesis in situ [129]. Recent research on the vascular system of BM has shown that patients with AML exhibit an elevated amount of MVD and that angiogenesis is closely associated with leukemogenesis. Moreover, patients with high baseline MVD were found to have a poorer prognosis, which aligns with observations in solid tumors [130]. On the other hand, MVD decreased dramatically on day sixteen post-chemotherapy induction in AML patients and it retained its normal level after complete remission (CR) had been achieved [131].

Various cytokines and signaling pathways have been implicated in malignant angiogenesis, including vascular endothelial growth factor (VEGF) and angiopoietins (ANGs). VEGF is secreted by AML cells to activate the VEGF receptor, which can be found in both AML and ECs. VEGF acts on ECs leading to stimulation of various growth factors like CSF3 and IL6 which enhance AML survival, angiogenesis, and proliferation [132]. Additionally, it was been found that VEGF has an anti-apoptotic effect as it activates the BCL2 family which acts as a shield protecting the leukemic cells from apoptosis [133]. Moreover, elevated plasma levels of VEGF in AML patients have been associated with a reduced survival rate and a lower incidence of achieving CR. Patients with increased VEGF expression also tend to have a shorter disease-free life [134]. Anti-VEGF (aflibercept) showed an increase in the OS in combination with doxorubicin in experimental studies [135]. Moreover, bevacizumab yields a favorable CR rate and duration in adults with AML patients who are resistant to traditional treatment approaches [136].

Another cytokine implicated in angiogenesis is the ANGs (ANG1 and ANG2) system. Patients with AML have higher levels of ANG in their serum and plasma, suggesting a potential role for ANG in leukemogenesis. The TIE2 receptor is activated by ANG1, which triggers the activation of the PI3KCA/AKT survival pathway, leading to the enhancement of EC viability. However, ANG2, an antagonist of ANG1, inhibits TIE2 activation, resulting in unstable vessels that are crucial for the onset of angiogenesis by VEGFA. Balanced and sequential expression of VEGF and ANGs is essential for effective angiogenesis. Additionally, high ANG2 level and ANG2/ANG1 ratio were found to be a predictive index for mortality from septic shock in acute leukemia patients with febrile neutropenia due to disturbance in small vessel permeability [137]. Moreover, AML vasculature shows an enhanced vascular permeability, that causes hindrance in the delivery of chemotherapy and turns the BMM into a haven for drug-resistant cells. Therefore, repairing the impaired vascular permeability can be used as an additional therapeutic technique alongside conventional chemotherapy [138, 139]. Trebananib is a neutralizing peptibody that prevents the interaction of ANGs with the TIE2 receptor [139]. It is highly recommended to use a standard angiogenic profile of each AML patient to determine their prognosis and select the most appropriate course of action. This can be achieved by choosing the right angiogenic therapy that targets multiple angiogenic factors. To facilitate multi-center investigations, a universal technique should be developed and applied for this purpose [126].

The leukemic endosteal niche promotes deficiency in bone mineralization delaying the maturation process of osteoblasts through several mechanisms. In AML, there is unchecked activation of the RANK/RANKL pathway, which is a crucial signaling pathway in bone remodeling, its activation leads to osteoclastogenesis and increases the survival of osteoclasts. There is a loss of fine-tuning between the bone resorption and formation in AML, the receptor activator of nuclear factor κB (RANK) is a transmembrane protein found on the surface of osteoclasts. On the other hand, the RANKL is a surface membrane protein expressed on the surface of osteoblast cells, stromal cells, and AML blasts [140].

For instance, the BM of mice with AML showed a decrease in osteoblastic cells, which worsened the disease by increasing the number of cancerous cells in circulation, increasing the tumor burden in the spleen and BM, and reducing the survival time of the mice. However, maintaining osteoblastic cells by using a serotonin synthesis inhibitor helped to return the BM to normal, decrease the number of tumors, and increase the survival rate of the mice [141].

Also, it has been demonstrated that AML cells stimulate osteoblastic differentiation while blocking adipogenic differentiation of MSCs by releasing bone morphogenetic protein (BMP) that activates SMAD1/5 signaling on MSCs to enhance osteoblast lineage differentiation. Additionally, osteopontin is an extracellular matrix protein produced that helps in the localization of HSC to the endosteal niche, it has been shown that leukemia decreases the levels of osteocalcin produced by osteoblasts and osteoclasts leading to a decrease in osteoblast and bone loss [142]. Several clinical trials investigated proteasome inhibitors like bortezomib [143], carfilzomib [144], and ixazomib [145] as targets for BM remodeling to promote osteoblast differentiation, suppress osteoclast activity, and induce apoptosis in leukemic cells. Moreover, cabozantinib, a receptor tyrosine kinase inhibitor that can inhibit osteoclast differentiation and resorption, modulates RANKL/osteoprotegerin in osteoblast, found to be well tolerated in AML and effectively inhibits the resistance‐conferring FLT3/tyrosine kinase domain/F691 mutation [146].

Despite the fact that MSCs in healthy individuals and AML patients usually express the same phenotypic markers, their functions, subtypes, and molecular profiles can be altered [141]. For example, expression of cell-surface molecules involved in interaction with HSCs is decreased, the number of CD271⁺ MSCs that facilitate LSCs proliferation is increased [147], and they harbor specific chromosomal and genetic aberrations that are different from that present in LSCs mostly in chromosome 1, 7, or, 10 [148]. Additionally, in patients with AML, RNA sequencing of BM MSCs at diagnosis unveiled dysregulation of adhesion molecules, cytokines, and proteoglycans, as well as changes in metabolic pathways, endocytosis, and transcriptional and epigenetic markers. MSCs although show overexpression of JAG1 and SCF down-regulation that decrease the support of normal hematopoiesis of HSCs. Moreover, LSCs reprogramme MSCs to enhance the expression of leukemogenesis-promoting factors such as CXCL12 and JAG1, and lower expression of genes associated with the cell cycle [149]. Notably, MSCs may play a critical role in AML relapse and chemotherapy resistance as they are associated with minimal residual disease persistence through supporting low proliferative but highly resistant LSCs [150]. It was demonstrated that co-culturing stromal cells with AML blasts inhibited both the cell contact-mediated route and the cytotoxic drug-induced apoptosis through MYC-dependent mechanisms, so targeting MYC pathway may serve as a potential tool to decrease drug resistance [151].

Through a highly regulated cross-talk between ECs and leukemic cells involving autocrine and paracrine stimuli, blast cells can create a unique environment that facilitates their own growth and survival [152]. This process has a profound impact on the pathophysiology of leukemia, as it allows the proliferation of these abnormal cells and the inhibition of normal cell growth. AML blast secretes various cytokines, such as IL1 beta and TNF alpha to enhance their attachment to the endothelium [153]. Several axes have been utilized, namely, CD44/selectin E and VLA4/VCAM1. When these adhesive mechanisms combine, it allows the migration of LSC through the vascular wall, leading to the anchoring of leukemic cells outside the BM. Encouraging studies have shown that antagonizing VCAM1 and selectin E can enhance myeloblast chemosensitivity and mobilization, which undermines their protection in the niche and ultimately reduces their survival [107]. Notably, the cross-talk between LSCs in AML and ECs enhances the process of angiogenesis through the DLL4 pathway [154]. Moreover, VEGF stimulates ECs to secrete CSF2 which stimulates AML cells and proliferation [155].

AML induces dramatic remodeling of BM vasculature through increased microvascular density [156]. Using advanced intravital microscopy two recent researches have demonstrated early, progressive, focal, and spatially non-random patterns of vascular remodeling in murine models of human AML with overall expansion of the endothelial compartment and BM microvascular density specific to engraftment of AML [138, 157]. Moreover, there is an expansion in arteriolar (CD31⁺Sca1^high) ECs and loss of those corresponding to sinusoids (CD31⁺Sca1^low). Notably, this aggressive vascular remodeling was associated with disrupted sinusoidal structure, reduced overall vessel diameter, increased vascular permeability, and induction of hypoxic BME [138].

At the molecular level, the analysis of the transcriptome of vascular ECs upon human AML engraftment confirms the toxic phenotype of the ECs. Additionally, gene set enrichment analysis revealed several altered processes directly associated with the abnormal vascular phenotype, including vasculature development, angiogenesis, and response to hypoxia. Of note, there is an extreme upregulation of integrins associated with Fak pathway activation in ECs. Moreover, enhanced expression of Nox4 in ECs and the increase production of ROS in the BM were observed [138].

BMAT has a controversial effect on normal hematopoiesis. On the other hand, the altered BMAT promotes the survival and proliferation of leukemic cells. AML cells introduce a lipolytic effect on BMAT leading to the release of free fatty acids that act as a source of nutrient supplements for leukemic cells [158]. Additionally, the adipogenic space in the BM cavity is decreased to allow uncontrolled expansion of leukemic cells [159]. leukemic cells are highly expressing growth differentiation factor 15 (GDF15) which may enhance the morphological alternation of a large adipocyte to a smaller version [160]. This lipolytic activity of GDF15 is promoted by the high expression of lipolytic genes such as LIPE and PNPLA2 [158].

A study by Tabe et al. [161] revealed that the cross-talk between acute monocytic leukemia cells and adipocytes exerts anti-apoptotic action through an increase in fatty acid β-oxidation (FAO) and upregulation of PPARG, FABP4, and BCL2 genes. Targeting BMAT remodeling in AML could serve as a therapeutic strategy for AML. For example, PPARG agonists could suppress leukemia proliferation and enhance normal hematopoiesis. Additionally, pharmacological inhibition of FAO could serve as a therapeutic target in AML such as avocatin B [162]. Furthermore, etomoxir, another FAO inhibitor showed an increased sensitivity to Ara-C in resistant AML cells [163].

Several studies elucidated that an altered BMM with SNS denervation enhances leukemic cell proliferation and turns the BMM inhospitable for normal HSCs. This manipulation is done indirectly through disruption of nestin GFP⁺ cell quiescence. Mutant nestin⁺ MSCs reduce the numbers of mature osteoblasts through β2-adrenergic signaling, resulting in a decrease of HSC-retention factors, such as CXCL12, SCF, ANG1, and VCAM1 [164]. It was found that administering a B2-adrenergic agonist led to a decrease in LSCs and increased the lifespan of mice with leukemia [164]. This suggests that changes to the B2-adrenergic pathway may have a role in the progression of leukemia. In conclusion, SNS can serve as a potential therapeutic target in AML.

It is a well-established fact that patients with hematological malignancies exhibit a remarkable ability of their immune system to identify and eliminate cancerous cells. However, the immune system’s natural restraint is ultimately compromised due to the presence of numerous immunosuppressive mechanisms, leading to widespread immunological dysregulation. This dysregulation culminates in the immune system’s failure to control cancerous cells, allowing them to proliferate and metastasize.