Remodeling of the bone marrow microenvironment during acute myeloid leukemia progression.

Hematopoiesis requires a complex interplay between the hematopoietic stem and progenitor cells and the cells of the bone marrow microenvironment (BMM). The BMM is heterogeneous, with different regions having distinct cellular, molecular, and metabolic composition and function. Studies have shown that this niche is disrupted in patients with acute myeloid leukemia (AML), which plays a crucial role in disease progression. This review provides a comprehensive overview of the components of vascular and endosteal niches and the molecular mechanisms by which they regulate normal hematopoiesis. We also discuss how these niches are modified in the context of AML, into a disease-promoting niche and how the modified niches in turn regulate AML blast survival and proliferation. We focus on mechanisms of modifications in structural and cellular components of the bone marrow (BM) niche by the AML cells and its impact on leukemic progression and patient outcome. Finally, we also discuss mechanisms by which the altered BM niche protects AML blasts from treatment agents, thereby causing therapy resistance in AML patients. We also summarize ongoing clinical trials that target various BM niche components in the treatment of AML patients. Hence, the BM niche represents a promising target to treat AML and promote normal hematopoiesis.

Role of Neurotransmitters in Steady State Hematopoiesis, Aging, and Leukemia.

Haematopoiesis within the bone marrow (BM) represents a complex and dynamic process intricately regulated by neural signaling pathways. This delicate orchestration is susceptible to disruption by factors such as aging, diabetes, and obesity, which can impair the BM niche and consequently affect haematopoiesis. Genetic mutations in Tet2, Dnmt3a, Asxl1, and Jak2 are known to give rise to clonal haematopoiesis of intermediate potential (CHIP), a condition linked to age-related haematological malignancies. Despite these insights, the exact roles of circadian rhythms, sphingosine-1-phosphate (S1P), stromal cell-derived factor-1 (SDF-1), sterile inflammation, and the complement cascade on various BM niche cells remain inadequately understood. Further research is needed to elucidate how BM niche cells contribute to these malignancies through neural regulation and their potential in the development of gene-corrected stem cells. This literature review describes the updated functional aspects of BM niche cells in haematopoiesis within the context of haematological malignancies, with a particular focus on neural signaling and the potential of radiomitigators in acute radiation syndrome. Additionally, it underscores the pressing need for technological advancements in stem cell-based therapies to alleviate the impacts of immunological stressors. Recent studies have illuminated the microheterogeneity and temporal stochasticity of niche cells within the BM during haematopoiesis, emphasizing the updated roles of neural signaling and immunosurveillance. The development of gene-corrected stem cells capable of producing blood, immune cells, and tissue-resident progeny is essential for combating age-related haematological malignancies and overcoming immunological challenges. This review aims to provide a comprehensive overview of these evolving insights and their implications for future therapeutic strategies.

Delivery of Therapeutic RNA to the Bone Marrow in Multiple Myeloma Using CD38-Targeted Lipid Nanoparticles.

Multiple myeloma (MM) is a cancer of differentiated plasma cells that occurs in the bone marrow (BM). Despite the recent advancements in drug development, most patients with MM eventually relapse and the disease remains incurable. RNA therapy delivered via lipid nanoparticles (LNPs) has the potential to be a promising cancer treatment, however, its clinical implementation is limited due to inefficient delivery to non-hepatic tissues. Here, targeted (t)LNPs designed for delivery of RNA payload to MM cells are presented. The tLNPs consist of a novel ionizable lipid and are coated with an anti-CD38 antibody (αCD38-tLNPs). To explore their therapeutic potential, it is demonstrated that LNPs encapsulating small interference RNA (siRNA) against cytoskeleton-associated protein 5 (CKAP5) lead to a ≈90% decrease in cell viability of MM cells in vitro. Next, a new xenograft MM mouse model is employed, which clinically resembles the human disease and demonstrates efficient homing of MM cells to the BM. Specific delivery of αCD38-tLNPs to BM-residing and disseminated MM cells and the improvement in therapeutic outcome of MM-bearing mice treated with αCD38-tLNPs-siRNA-CKAP5 are shown. These results underscore the potential of RNA therapeutics for treatment of MM and the importance of developing effective targeted delivery systems and reliable preclinical models.

Regulatory T cell niche in the bone marrow, a new player in Haematopoietic stem cell transplantation.

Challenges in haematopoietic stem cell transplantation such as low bone marrow (BM) engraftment, graft versus host disease (GvHD) and the need for long-term immunosuppression could be addressed using T regulatory cells (Tregs) resident in the tissue of interest, in this case, BM Tregs. Controlling the adverse immune response in haematopoietic stem cell transplantation (HSCT) and minimising the associated risks such as infection and secondary cancers due to long-term immunosuppression is a crucial aspect of clinical practice in this field. While systemic immunosuppressive therapy could achieve reasonable GvHD control in most patients, related side effects remain the main limiting factor. Developing more targeted immunosuppressive strategies is an unmet clinical need and is the focus of several ongoing research projects. Tregs are a non-redundant sub-population of CD4+ T cells essential for controlling the immune homeostasis. Tregs are known to be reduced in number and function in autoimmune conditions. There is considerable interest in these cells as cell therapy products since they can be expanded in vitro and infused into patients. These trials have found Treg therapy to be safe, well-tolerated, and with some early signs of efficacy. However, Tregs are a heterogeneous subpopulation of T cells, and several novel subpopulations have been identified in recent years beyond the conventional thymic (tTregs) and peripheral (pTregs). There is increasing evidence for the presence of resident and tissue-specific Tregs. Bone marrow (BM) Tregs are one example of tissue-resident Tregs. BM Tregs are enriched within the marrow, serving a dual function of immunosuppression and maintenance of haematopoietic stem cells (HSCs). HSCs maintenance is achieved through direct suppression of HSCs differentiation, maintaining a proliferating pool of HSCs, and promoting the development of functional stromal cells that support HSCs. In this review, we will touch upon the biology of Tregs, focusing on their development and heterogeneity. We will focus on the BM Tregs from their biology to their therapeutic potential, focusing on their use in HSCT.

Mesenchymal Stromal Cells (MSCs): An Ally of B-Cell Acute Lymphoblastic Leukemia (B-ALL) Cells in Disease Maintenance and Progression within the Bone Marrow Hematopoietic Niche.

Mesenchymal stromal cells (MSCs) are structural components of the bone marrow (BM) niche, where they functionally interact with hematopoietic stem cells and more differentiated progenitors, contributing to hematopoiesis regulation. A growing body of evidence is nowadays pointing to a further crucial contribution of MSCs to malignant hematopoiesis. In the context of B-cell acute lymphoblastic leukemia (B-ALL), MSCs can play a pivotal role in the definition of a leukemia-supportive microenvironment, impacting on disease pathogenesis at different steps including onset, maintenance and progression. B-ALL cells hijack the BM microenvironment, including MSCs residing in the BM niche, which in turn shelter leukemic cells and protect them from chemotherapeutic agents through different mechanisms. Evidence is now arising that altered MSCs can become precious allies to leukemic cells by providing nutrients, cytokines, pro-survivals signals and exchanging organelles, as hereafter reviewed. The study of the mechanisms exploited by MSCs to nurture and protect B-ALL blasts can be instrumental in finding new druggable candidates to target the leukemic BM microenvironment. Some of these microenvironment-targeting strategies are already in preclinical or clinical experimentation, and if coupled with leukemia-directed therapies, could represent a valuable option to improve the prognosis of relapsed/refractory patients, whose management represents an unmet medical need.

The Bone Marrow Niche in B-Cell Acute Lymphoblastic Leukemia: The Role of Microenvironment from Pre-Leukemia to Overt Leukemia.

Genetic lesions predisposing to pediatric B-cell acute lymphoblastic leukemia (B-ALL) arise in utero, generating a clinically silent pre-leukemic phase. We here reviewed the role of the surrounding bone marrow (BM) microenvironment in the persistence and transformation of pre-leukemic clones into fully leukemic cells. In this context, inflammation has been highlighted as a crucial microenvironmental stimulus able to promote genetic instability, leading to the disease manifestation. Moreover, we focused on the cross-talk between the bulk of leukemic cells with the surrounding microenvironment, which creates a "corrupted" BM malignant niche, unfavorable for healthy hematopoietic precursors. In detail, several cell subsets, including stromal, endothelial cells, osteoblasts and immune cells, composing the peculiar leukemic niche, can actively interact with B-ALL blasts. Through deregulated molecular pathways they are able to influence leukemia development, survival, chemoresistance, migratory and invasive properties. The concept that the pre-leukemic and leukemic cell survival and evolution are strictly dependent both on genetic lesions and on the external signals coming from the microenvironment paves the way to a new idea of dual targeting therapeutic strategy.

Kindlin-3 loss curbs chronic myeloid leukemia in mice by mobilizing leukemic stem cells from protective bone marrow niches.

Kindlin-3 (K3)-mediated integrin adhesion controls homing and bone marrow (BM) retention of normal hematopoietic cells. However, the role of K3 in leukemic stem cell (LSC) retention and growth in the remodeled tumor-promoting BM is unclear. We report that loss of K3 in a mouse model of chronic myeloid leukemia (CML) triggers the release of LSCs from the BM into the circulation and impairs their retention, proliferation, and survival in secondary organs, which curbs CML development, progression, and metastatic dissemination. We found de novo expression of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) on CML-LSCs but not normal hematopoietic stem cells and this enabled us to specifically deplete K3 with a CTLA-4-binding RNA aptamer linked to a K3-siRNA (small interfering RNA) in CTLA-4+ LSCs in vivo, which mobilized LSCs in the BM, induced disease remission, and prolonged survival of mice with CML. Thus, disrupting interactions of LSCs with the BM environment is a promising strategy to halt the disease-inducing and relapse potential of LSCs.

Mesenchymal Stromal Cells as a Cellular Target in Myeloid Malignancy: Chances and Challenges in the Genome Editing of Stromal Alterations.

The contribution of bone marrow stromal cells to the pathogenesis and therapy response of myeloid malignancies has gained significant attention over the last decade. Evidence suggests that the bone marrow stroma should not be neglected in the design of novel, targeted-therapies. In terms of gene-editing, the focus of gene therapies has mainly been on correcting mutations in hematopoietic cells. Here, we outline why alterations in the stroma should also be taken into consideration in the design of novel therapeutic strategies but also outline the challenges in specifically targeting mesenchymal stromal cells in myeloid malignancies caused by somatic and germline mutations.

Mobilized peripheral blood: an updated perspective.

Enforced egress of hematopoietic stem cells (HSCs) out of the bone marrow (BM) into the peripheral circulation, termed mobilization, has come a long way since its discovery over four decades ago. Mobilization research continues to be driven by the need to optimize the regimen currently available in the clinic with regard to pharmacokinetic and pharmacodynamic profile, costs, and donor convenience. In this review, we describe the most recent findings in the field and how we anticipate them to affect the development of mobilization strategies in the future. Furthermore, the significance of mobilization beyond HSC collection, i.e. for chemosensitization, conditioning, and gene therapy as well as a means to study the interactions between HSCs and their BM microenvironment, is reviewed. Open questions, controversies, and the potential impact of recent technical progress on mobilization research are also highlighted.

The Instructive Role of the Bone Marrow Niche in Aging and Leukemia.

PURPOSE OF REVIEW: In this review, we aim to discuss the role of the bone marrow microenvironment in supporting hematopoiesis, with particular focus on the contribution of the endothelial niche in dictating hematopoietic stem cell (HSC) fate. RECENT FINDINGS: Evidence gathered in the past two decades revealed that specific cell types within the bone marrow niche influence the hematopoietic system. Endothelial cells have emerged as a key component of the HSC niche, directly affecting stem cell quiescence, self-renewal, and lineage differentiation. Physiological alterations of the bone marrow niche occurring in aging have been described to be sufficient to promote functional aging of young HSCs. Furthermore, a growing body of evidence suggests that aberrant activation of endothelial-derived signaling pathways can aid or trigger neoplastic transformation. SUMMARY: Several groups have contributed to the characterization of the different cell types that comprise the complex bone marrow environment, whose function was long perceived as an undiscernible sum of many parts. Further studies will need to uncover niche cell-type-specific pathways, in order to provide new targets and therapeutic options that aim at withdrawing the microenvironmental support to malignant cells while sparing normal HSCs.

Understanding of leukemic stem cells and their clinical implications.

Since leukemic stem cells (LSCs) or cancer stem cells (CSCs) were found in acute myeloid leukemia (AML) in 1997, extensive studies have been contributed to identification and characterization of such cell populations in various tissues. LSCs are now generally recognized as a heterogeneous cell population that possesses the capacities of self-renewal, proliferation and differentiation. It has been shown that LSCs are regulated by critical surface antigens, microenvironment, intrinsic signaling pathways, and novel molecules such as some ncRNAs. To date, significant progress has been made in understanding of LSCs, leading to the development of numerous LSCs-targeted therapies. Moreover, various novel therapeutic agents targeting LSCs are undergoing clinical trials. Here, we review current knowledge of LSCs, and discuss the potential therapies and their challenges that are being tested in clinical trials for evaluation of their effects on leukemias.

Role of the bone morphogenic protein pathway in developmental haemopoiesis and leukaemogenesis.

Myeloid leukaemias share the common characteristics of being stem cell-derived clonal diseases, characterised by excessive proliferation of one or more myeloid lineage. Chronic myeloid leukaemia (CML) arises from a genetic alteration in a normal haemopoietic stem cell (HSC) giving rise to a leukaemic stem cell (LSC) within the bone marrow (BM) 'niche'. CML is characterised by the presence of the oncogenic tyrosine kinase fusion protein breakpoint cluster region-abelson murine leukaemia viral oncogene homolog 1 (BCR-ABL), which is responsible for driving the disease through activation of downstream signal transduction pathways. Recent evidence from our group and others indicates that important regulatory networks involved in establishing primitive and definitive haemopoiesis during development are reactivated in myeloid leukaemia, giving rise to an LSC population with altered self-renewal and differentiation properties. In this review, we explore the role the bone morphogenic protein (BMP) signalling plays in stem cell pluripotency, developmental haemopoiesis, HSC maintenance and the implication of altered BMP signalling on LSC persistence in the BM niche. Overall, we emphasise how the BMP and Wnt pathways converge to alter the Cdx-Hox axis and the implications of this in the pathogenesis of myeloid malignancies.