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Cancers Jun 2023Myeloid leukemia of Down syndrome (ML-DS) is characterized by a distinct natural history and is classified by the World Health Organization (WHO) as an independent... (Review)
Review
Myeloid leukemia of Down syndrome (ML-DS) is characterized by a distinct natural history and is classified by the World Health Organization (WHO) as an independent entity, occurring with unique clinical and molecular features. The presence of a long preleukemic, myelodysplastic phase, called transient abnormal myelopoiesis (TAM), precedes the initiation of ML-DS and is defined by unusual chromosomal findings. Individuals with constitutional trisomy 21 have a profound dosage imbalance in the hematopoiesis-governing genes located on chromosome 21 and thus are subject to impaired fetal as well as to neonatal erythro-megakaryopoiesis. Almost all neonates with DS develop quantitative and morphological hematological abnormalities, yet still only 5-10% of them present with one of the preleukemic or leukemic conditions of DS. The acquired mutations in the key hematopoietic transcription factor gene , found solely in cells trisomic for chromosome 21, are considered to be the essential step for the selective growth advantage of leukemic cells. While the majority of cases of TAM remain clinically 'silent' or undergo spontaneous remission, the remaining 20% to 30% of them progress into ML-DS until the age of 4 years. The hypersensitivity of ML-DS blasts to chemotherapeutic agents, including but not limited to cytarabine, and drugs' increased infectious and cardiac toxicity have necessitated the development of risk-adapted treatment protocols for children with ML-DS. Recent advances in cytogenetics and specific molecular mechanisms involved in the evolution of TAM and ML-DS are reviewed here, as well as their integration in the improvement of risk stratification and targeted management of ML-DS.
PubMed: 37444375
DOI: 10.3390/cancers15133265 -
Molecular Aspects of Medicine Feb 2021Hematopoietic stem cells (HSC) lie at the center of the hematopoiesis process, as they bear capacity to self-renew and generate all hematopoietic lineages, hence, all... (Review)
Review
Hematopoietic stem cells (HSC) lie at the center of the hematopoiesis process, as they bear capacity to self-renew and generate all hematopoietic lineages, hence, all mature blood cells. The ability of HSCs to recognize systemic infection or inflammation or other forms of peripheral stress, such as blood loss, is essential for demand-adapted hematopoiesis. Also of critical importance for HSC function, specific metabolic cues (e.g., associated with changes in energy or O levels) can regulate HSC function and fate decisions. In this regard, the metabolic adaptation of HSCs facilitates their switching between different states, namely quiescence, self-renewal, proliferation and differentiation. Specific metabolic alterations in hematopoietic stem and progenitor cells (HSPCs) have been linked with the induction of trained myelopoiesis in the bone marrow as well as with HSPC dysfunction in aging and clonal hematopoiesis of indeterminate potential (CHIP). Thus, HSPC function is regulated by both immunologic/inflammatory and metabolic cues. The immunometabolic control of HSPCs and of hematopoiesis is discussed in this review along with the translational implications thereof, that is, how metabolic pathways can be therapeutically manipulated to prevent or reverse HSPC dysfunction or to enhance or attenuate trained myelopoiesis according to the needs of the host.
Topics: Cell Differentiation; Cell Proliferation; Hematopoiesis; Hematopoietic Stem Cells; Humans; Inflammation
PubMed: 33160640
DOI: 10.1016/j.mam.2020.100923 -
Cancers Apr 2021We have recently described physiological expression patterns of NKL homeobox genes in early hematopoiesis and in subsequent lymphopoiesis and myelopoiesis, including... (Review)
Review
We have recently described physiological expression patterns of NKL homeobox genes in early hematopoiesis and in subsequent lymphopoiesis and myelopoiesis, including terminally differentiated blood cells. We thereby systematized differential expression patterns of eleven such genes which form the so-called NKL-code. Due to the developmental impact of NKL homeobox genes, these data suggest a key role for their activity in normal hematopoietic differentiation processes. On the other hand, the aberrant overexpression of NKL-code-members or the ectopical activation of non-code members have been frequently reported in lymphoid and myeloid leukemia/lymphoma, revealing the oncogenic potential of these genes in the hematopoietic compartment. Here, I provide an overview of the NKL-code in normal hematopoiesis and instance mechanisms of deregulation and oncogenic functions of selected NKL genes in hematologic cancers. As well as published clinical studies, our conclusions are based on experimental work using hematopoietic cell lines which represent useful models to characterize the role of NKL homeobox genes in specific tumor types.
PubMed: 33921702
DOI: 10.3390/cancers13081961 -
Current Opinion in Lipidology Oct 2019Monocytes and macrophages are key players in the pathogenesis of atherosclerosis and dictate atherogenesis growth and stability. The heterogeneous nature of myeloid... (Review)
Review
PURPOSE OF REVIEW
Monocytes and macrophages are key players in the pathogenesis of atherosclerosis and dictate atherogenesis growth and stability. The heterogeneous nature of myeloid cells concerning their metabolic and phenotypic function is increasingly appreciated. This review summarizes the recent monocyte and macrophage literature and highlights how differing subsets contribute to atherogenesis.
RECENT FINDINGS
Monocytes are short-lived cells generated in the bone marrow and released to circulation where they can produce inflammatory cytokines and, importantly, differentiate into long-lived macrophages. In the context of cardiovascular disease, a myriad of subtypes, exist with each differentially contributing to plaque development. Herein we describe recent novel characterizations of monocyte and macrophage subtypes and summarize the recent literature on mediators of myelopoiesis.
SUMMARY
An increased understanding of monocyte and macrophage phenotype and their molecular regulators is likely to translate to the development of new therapeutic targets to either stem the growth of existing plaques or promote plaque stabilization.
Topics: Atherosclerosis; Bone Marrow Cells; Cell Differentiation; Cytokines; Humans; Macrophages; Monocytes; Myelopoiesis; Plaque, Atherosclerotic
PubMed: 31361625
DOI: 10.1097/MOL.0000000000000634 -
Nature Cell Biology Dec 2023Myeloid cell infiltration of solid tumours generally associates with poor patient prognosis and disease severity. Therefore, understanding the regulation of myeloid cell...
Myeloid cell infiltration of solid tumours generally associates with poor patient prognosis and disease severity. Therefore, understanding the regulation of myeloid cell differentiation during cancer is crucial to counteract their pro-tumourigenic role. Bone marrow (BM) haematopoiesis is a tightly regulated process for the production of all immune cells in accordance to tissue needs. Myeloid cells differentiate during haematopoiesis from multipotent haematopoietic stem and progenitor cells (HSPCs). HSPCs can sense inflammatory signals from the periphery during infections or inflammatory disorders. In these settings, HSPC expansion is associated with increased myeloid differentiation. During carcinogenesis, the elevation of haematopoietic growth factors supports the expansion and differentiation of committed myeloid progenitors. However, it is unclear whether cancer-related inflammation also triggers demand-adapted haematopoiesis at the level of multipotent HSPCs. In the BM, HSPCs reside within the haematopoietic niche which delivers HSC maintenance and differentiation cues. Mesenchymal stem cells (MSCs) are a major cellular component of the BM niche and contribute to HSC homeostasis. Modifications of MSCs in systemic disorders have been associated with HSC differentiation towards myeloid cells. It is unknown if MSCs are regulated in the context of solid tumours and if their myeloid supportive activity is impacted by cancer-induced systemic changes. Here, using unbiased transcriptomic analysis and in situ imaging of HSCs and the BM niche during breast cancer, we show that both HSCs and MSCs are transcriptionally and spatially modified. We demonstrate that breast tumour can distantly remodel the cellular cross-talks in the BM niche leading to increased myelopoiesis.
Topics: Humans; Female; Bone Marrow; Breast Neoplasms; Hematopoietic Stem Cells; Multipotent Stem Cells; Cell Differentiation; Stem Cell Niche; Bone Marrow Cells
PubMed: 38036749
DOI: 10.1038/s41556-023-01291-w -
Radiographics : a Review Publication of... 2020Fetal hepatomegaly is associated with significant fetal morbidity and mortality. However, hepatomegaly might be overlooked when numerous other fetal anomalies are... (Review)
Review
Fetal hepatomegaly is associated with significant fetal morbidity and mortality. However, hepatomegaly might be overlooked when numerous other fetal anomalies are present, or it might not be noticed when it is an isolated entity. As the largest solid organ in the abdomen, the liver can be seen well with US or MRI, and the normal imaging characteristics are well described. The length of the fetal liver, which can be used to identify hepatomegaly, can be determined by measuring the liver from the diaphragm to the tip of the right lobe in the sagittal plane. Fetal hepatomegaly is seen with infection, transient abnormal myelopoiesis, liver storage and deposition diseases, some syndromes, large liver tumors, biliary atresia, and anemia. Some of these diagnoses are treatable during the fetal period. Attention to the associated findings and specific hepatic and nonhepatic imaging characteristics can help facilitate more accurate diagnoses and appropriate patient counseling.RSNA, 2020.
Topics: Diagnosis, Differential; Female; Fetal Diseases; Hepatomegaly; Humans; Pregnancy
PubMed: 32125959
DOI: 10.1148/rg.2020190114 -
BioRxiv : the Preprint Server For... Mar 2024The bone marrow is the organ responsible for blood production. Diverse non-hematopoietic cells contribute essentially to hematopoiesis. However, these cells and their...
The bone marrow is the organ responsible for blood production. Diverse non-hematopoietic cells contribute essentially to hematopoiesis. However, these cells and their spatial organization remain largely uncharacterized as they have been technically challenging to study in humans. Here, we used fresh femoral head samples and performed single-cell RNA sequencing (scRNA-Seq) to profile 29,325 enriched non-hematopoietic bone marrow cells and discover nine transcriptionally distinct subtypes. We next employed CO-detection by inDEXing (CODEX) multiplexed imaging of 18 individuals, including both healthy and acute myeloid leukemia (AML) samples, to spatially profile over one million single cells with a novel 53-antibody panel. We discovered a relatively hyperoxygenated arterio-endosteal niche for early myelopoiesis, and an adipocytic, but not endosteal or perivascular, niche for early hematopoietic stem and progenitor cells. We used our atlas to predict cell type labels in new bone marrow images and used these predictions to uncover mesenchymal stromal cell (MSC) expansion and leukemic blast/MSC-enriched spatial neighborhoods in AML patient samples. Our work represents the first comprehensive, spatially-resolved multiomic atlas of human bone marrow and will serve as a reference for future investigation of cellular interactions that drive hematopoiesis.
PubMed: 38559168
DOI: 10.1101/2024.03.14.585083 -
Nature Reviews. Immunology Mar 2020Genetic defects that accumulate in haematopoietic stem cells (HSCs) are thought to be responsible for age-related changes in haematopoiesis that include a decline in... (Review)
Review
Genetic defects that accumulate in haematopoietic stem cells (HSCs) are thought to be responsible for age-related changes in haematopoiesis that include a decline in lymphopoiesis and skewing towards the myeloid lineage. This HSC-centric view is based largely on studies showing that HSCs from aged mice exhibit these lineage biases following transplantation into irradiated young recipient mice. In this Opinion article, we make the case that the reliance on this approach has led to inaccurate conclusions regarding the effects of ageing on blood-forming stem cells; we suggest instead that changes in the environment contribute to haematopoietic system ageing. We propose that a complete understanding of how ageing affects haematopoiesis depends on the analysis of blood cell production in unperturbed mice. We describe how this can be achieved using in situ fate mapping. This approach indicates that changes in downstream progenitors, in addition to any HSC defects, may explain the reduced lymphopoiesis and sustained myelopoiesis that occur during ageing.
Topics: Aging; Animals; Cell Differentiation; Cell Lineage; Cellular Senescence; Hematopoiesis; Hematopoietic Stem Cells; Humans; Myelopoiesis
PubMed: 31740804
DOI: 10.1038/s41577-019-0236-2 -
Circulation Research Sep 2020
Topics: Atherosclerosis; Humans; Hyperglycemia; Myelopoiesis
PubMed: 32910740
DOI: 10.1161/CIRCRESAHA.120.317797 -
Cell Regeneration (London, England) Jan 2023Myelopoiesis is the process in which the mature myeloid cells, including monocytes/macrophages and granulocytes, are developed. Irregular myelopoiesis may cause and... (Review)
Review
Myelopoiesis is the process in which the mature myeloid cells, including monocytes/macrophages and granulocytes, are developed. Irregular myelopoiesis may cause and deteriorate a variety of hematopoietic malignancies such as leukemia. Myeloid cells and their precursors are difficult to capture in circulation, let alone observe them in real time. For decades, researchers had to face these difficulties, particularly in in-vivo studies. As a unique animal model, zebrafish possesses numerous advantages like body transparency and convenient genetic manipulation, which is very suitable in myelopoiesis research. Here we review current knowledge on the origin and regulation of myeloid development and how zebrafish models were applied in these studies.
PubMed: 36595106
DOI: 10.1186/s13619-022-00139-2