-
International Immunopharmacology Jun 2024Tumor microenvironment (TME), is characterized by a complex and heterogenous composition involving a substantial population of immune cells. Myeloid cells comprising... (Review)
Review
Tumor microenvironment (TME), is characterized by a complex and heterogenous composition involving a substantial population of immune cells. Myeloid cells comprising over half of the solid tumor mass, are undoubtedly one of the most prominent cell populations associated with tumors. Studies have unambiguously established that myeloid cells play a key role in tumor development, including immune suppression, pro-inflammation, promote tumor metastasis and angiogenesis, for example, tumor-associated macrophages promote tumor progression in a variety of common tumors, including lung cancer, through direct or indirect interactions with the TME. However, due to previous technological constraints, research on myeloid cells often tended to be conducted as studies with low throughput and limited resolution. For example, the conventional categorization of macrophages into M1-like and M2-like subsets based solely on their anti-tumor and pro-tumor roles has disregarded their continuum of states, resulting in an inadequate analysis of the high heterogeneity characterizing myeloid cells. The widespread adoption of single-cell RNA sequencing (scRNA-seq) in tumor immunology has propelled researchers into a new realm of understanding, leading to the establishment of novel subsets and targets. In this review, the origin of myeloid cells in high-incidence cancers, the functions of myeloid cell subsets examined through traditional and single-cell perspectives, as well as specific targeting strategies, are comprehensively outlined. As a result of this endeavor, we will gain a better understanding of myeloid cell heterogeneity, as well as contribute to the development of new therapeutic approaches.
Topics: Humans; Tumor Microenvironment; Neoplasms; Myeloid Cells; Animals; Single-Cell Analysis
PubMed: 38735257
DOI: 10.1016/j.intimp.2024.112253 -
Journal of Neonatal-perinatal Medicine 2024Tumor lysis syndrome (TLS) is an oncological emergency associated with hematological malignancies or highly proliferative solid tumors, commonly after chemotherapy. It...
BACKGROUND
Tumor lysis syndrome (TLS) is an oncological emergency associated with hematological malignancies or highly proliferative solid tumors, commonly after chemotherapy. It is rarely associated with transient abnormal myelopoiesis.
OBSERVATION
We report a rare case of a neonate with transient abnormal myelopoiesis and tumor lysis syndrome, complicated with concomitant heart failure due to an underlying atrioventricular septal defect. Hyperhydration was contraindicated due to heart failure. The patient was managed conservatively with full recovery.
CONCLUSION
Tumor lysis syndrome should be suspected in neonates with transient abnormal myelopoiesis with electrolyte abnormalities. Treatment options should be considered carefully for their risks and benefits.
Topics: Humans; Tumor Lysis Syndrome; Infant, Newborn; Leukemoid Reaction; Heart Failure; Male; Female; Heart Septal Defects, Atrial; Down Syndrome
PubMed: 38728206
DOI: 10.3233/NPM-230146 -
Critical Reviews in Oncology/hematology Jul 2024Transient abnormal myelopoiesis (TAM) in neonates with Down syndrome is a distinct form of leukemia or preleukemia that mirrors the hematological features of acute... (Review)
Review
Transient abnormal myelopoiesis (TAM) in neonates with Down syndrome is a distinct form of leukemia or preleukemia that mirrors the hematological features of acute megakaryoblastic leukemia. However, it typically resolves spontaneously in the early stages. TAM originates from fetal liver (FL) hematopoietic precursor cells and emerges due to somatic mutations in GATA1 in utero. In TAM, progenitor cells proliferate and differentiate into mature megakaryocytes and granulocytes. This process occurs both in vitro, aided by hematopoietic growth factors (HGFs) produced in the FL, and in vivo, particularly in specific anatomical sites like the FL and blood vessels. The FL's hematopoietic microenvironment plays a crucial role in TAM's pathogenesis and may contribute to its spontaneous regression. This review presents an overview of current knowledge regarding the unique features of TAM in relation to the FL hematopoietic microenvironment, focusing on the functions of HGFs and the pathological features of TAM.
Topics: Humans; Down Syndrome; Liver; Leukemoid Reaction; Hematopoietic Stem Cells; Fetus; GATA1 Transcription Factor; Myelopoiesis
PubMed: 38723838
DOI: 10.1016/j.critrevonc.2024.104382 -
Cell Jun 2024Non-hematopoietic cells are essential contributors to hematopoiesis. However, heterogeneity and spatial organization of these cells in human bone marrow remain largely...
Non-hematopoietic cells are essential contributors to hematopoiesis. However, heterogeneity and spatial organization of these cells in human bone marrow remain largely uncharacterized. We used single-cell RNA sequencing (scRNA-seq) to profile 29,325 non-hematopoietic cells and discovered nine transcriptionally distinct subtypes. We simultaneously profiled 53,417 hematopoietic cells and predicted their interactions with non-hematopoietic subsets. We employed co-detection by indexing (CODEX) to spatially profile over 1.2 million cells. We integrated scRNA-seq and CODEX data to link predicted cellular signaling with spatial proximity. Our analysis revealed a hyperoxygenated arterio-endosteal neighborhood for early myelopoiesis, and an adipocytic localization for early hematopoietic stem and progenitor cells (HSPCs). We used our CODEX atlas to annotate new images and uncovered mesenchymal stromal cell (MSC) expansion and spatial neighborhoods co-enriched for leukemic blasts and MSCs in acute myeloid leukemia (AML) patient samples. This spatially resolved, multiomic atlas of human bone marrow provides a reference for investigation of cellular interactions that drive hematopoiesis.
Topics: Humans; Single-Cell Analysis; Bone Marrow; Hematopoietic Stem Cells; Mesenchymal Stem Cells; Proteomics; Transcriptome; Leukemia, Myeloid, Acute; Hematopoiesis; Stem Cell Niche; Bone Marrow Cells
PubMed: 38714197
DOI: 10.1016/j.cell.2024.04.013 -
Cell Death Discovery May 2024Hematopoiesis ensures tissue oxygenation, and remodeling as well as immune protection in vertebrates. During embryogenesis, hemangioblasts are the source of all blood...
Hematopoiesis ensures tissue oxygenation, and remodeling as well as immune protection in vertebrates. During embryogenesis, hemangioblasts are the source of all blood cells. Gata1a and pu.1 are co-expressed in hemangioblasts before hemangioblasts are differentiated into blood cells. However, the genes that determine the differentiation of hemangioblasts into myeloid or erythroid cell lineages have not been fully uncovered. Here we showed that miRNA-7145, a miRNA with previously unknown function, was enriched in erythrocytes at the definitive wave, but not expressed in myeloid cells. Overexpression and loss-of-function analysis of miRNA-7145 revealed that miRNA-7145 functions as a strong inhibitor for myeloid progenitor cell differentiation while driving erythropoiesis during the primitive wave. Furthermore, we confirmed that cuedc2 is one of miRNA-7145 targeted-genes. Overexpression or knock-down of cuedc2 partially rescues the phenotype caused by miRNA-7145 overexpression or loss-of-function. As well, overexpression and loss-of-function analysis of cuedc2 showed that cuedc2 is required for myelopoiesis at the expense of erythropoiesis. Finally, we found that overexpression of zebrafish cuedc2 in 293 T cell inhibits the JAK1/STAT3 signaling pathway. Collectively, our results uncover a previously unknown miRNA-7145-cuedc2 axis, which regulate hematopoiesis through inhibiting the JAK1/STAT3 signaling pathway.
PubMed: 38697957
DOI: 10.1038/s41420-024-01977-6 -
Blood Advances Jun 2024Transient abnormal myelopoiesis (TAM) occurs in 10% of neonates with Down syndrome (DS). Although most patients show spontaneous resolution of TAM, early death occurs in... (Clinical Trial)
Clinical Trial
Transient abnormal myelopoiesis (TAM) occurs in 10% of neonates with Down syndrome (DS). Although most patients show spontaneous resolution of TAM, early death occurs in ∼20% of cases. Therefore, new biomarkers are needed to predict early death and determine therapeutic interventions. This study aimed to determine the association between clinical characteristics and cytokine levels in patients with TAM. A total of 128 patients with DS with TAM enrolled in the TAM-10 study conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group were included in this study. Five cytokine levels (interleukin-1b [IL-1b], IL-1 receptor agonist, IL-6, IL-8, and IL-13) were significantly higher in patients with early death than in those with nonearly death. Cumulative incidence rates (CIRs) of early death were significantly associated with high levels of the 5 cytokines. Based on unsupervised consensus clustering, patients were classified into 3 cytokine groups: hot-1 (n = 37), hot-2 (n = 42), and cold (n = 49). The CIR of early death was significantly different between the cytokine groups (hot-1/2, n = 79; cold, n = 49; hot-1/2 CIR, 16.5% [95% confidence interval (CI), 7.9-24.2]; cold CIR, 2.0% [95% CI, 0.0-5.9]; P = .013). Furthermore, cytokine groups (hot-1/2 vs cold) were independent poor prognostic factors in the multivariable analysis for early death (hazard ratio, 15.53; 95% CI, 1.434-168.3; P = .024). These results provide valuable information that cytokine level measurement was useful in predicting early death in patients with TAM and might help to determine the need for therapeutic interventions. This trial was registered at UMIN Clinical Trials Registry as #UMIN000005418.
Topics: Humans; Cytokines; Male; Female; Leukemoid Reaction; Down Syndrome; Infant; Child, Preschool; Biomarkers; Infant, Newborn; Child; Myelopoiesis; Prognosis
PubMed: 38691583
DOI: 10.1182/bloodadvances.2023011628 -
[Rinsho Ketsueki] the Japanese Journal... 2024Myelodysplastic syndromes (MDS) are a group of heterogenous hematopoietic stem cell (HSC) malignancies characterized by ineffective hematopoiesis in which clonal...
Myelodysplastic syndromes (MDS) are a group of heterogenous hematopoietic stem cell (HSC) malignancies characterized by ineffective hematopoiesis in which clonal progenitor expansion occurs alongside impaired myelopoiesis. Inflammatory signaling activation due to dysregulated innate immunity is also a hallmark of MDS pathogenesis. We recently established a useful preclinical tool that recapitulates bona fide MDS phenotypes and gene expression profiles based on previously unreported co-mutations discovered during our clinical surveillance of mutations in patients with MDS. Notably, we focused unbiased transcriptome analysis on determining the distinct underlying mediators of MDS etiology, and identified excessive mitochondrial fission-mediated fragmentation in mutant HSCs and progenitors (HSC/Ps). We confirmed excessive mitochondrial fragmentation in HSC/Ps obtained from patients with MDS regardless of the mutational profile. Importantly, in vivo pharmacological inhibition of mitochondrial fission significantly attenuated inflammatory signaling activation, dysplasia formation and ineffective hematopoiesis phenotype, and prolonged survival of MDS mice, suggesting that excessive mitochondrial fragmentation could be a fundamental trigger of MDS pathogenesis. These findings provide new insights into the mechanistic basis of ineffective hematopoiesis, and a clue for targeting bone marrow failure caused by ineffective hematopoiesis in MDS.
Topics: Myelodysplastic Syndromes; Humans; Animals; Mitochondria; Mutation
PubMed: 38684435
DOI: 10.11406/rinketsu.65.249 -
Journal of Leukocyte Biology Apr 2024The noncanonical NF-κB pathway is involved in lymphoid organ development, B cell maturation, and cytokine production. However, new research has demonstrated that this...
The noncanonical NF-κB pathway is involved in lymphoid organ development, B cell maturation, and cytokine production. However, new research has demonstrated that this pathway is also key for the orderly and sequential maturation of myeloid cells, including neutrophils and eosinophils. When this pathway is disrupted or constitutively activated, aberrations in hematopoietic stem and progenitor cell (HSPC) survival and proliferation, as well as subsequent granulopoiesis and eosinophilopoiesis are affected. Disturbance of such a coordinated and delicate process can manifest in devastating clinical disease including acute and chronic myeloid leukemias (AML and CML, respectively), pre-leukemic processes such as myelodysplastic syndrome (MDS) or hyperinflammatory conditions like Hypereosinophilic Syndrome (HES). In this review, we will discuss the molecular machinery within the noncanonical NF-κB pathway, crosstalk with the canonical NF-κB pathway, murine models of noncanonical signaling, as well as how aberrations in this pathway manifest in leukemic or hyperinflammatory disease with a focus on HES. Potential and promising drug therapies will also be discussed, emphasizing the noncanonical NF-κB pathway as a potential target for improved treatment for patients suffering from leukemia or idiopathic HES. The hope is that review of such mechanisms and treatments may eventually result in findings that aid physicians in rapidly diagnosing and more accurately classifying patients suffering from such complex and overlapping hematopoietic diseases.
PubMed: 38682253
DOI: 10.1093/jleuko/qiae101 -
Frontiers in Immunology 2024The recent identification of skull bone marrow as a reactive hematopoietic niche that can contribute to and direct leukocyte trafficking into the meninges and brain has... (Review)
Review
The recent identification of skull bone marrow as a reactive hematopoietic niche that can contribute to and direct leukocyte trafficking into the meninges and brain has transformed our view of this bone structure from a solid, protective casing to a living, dynamic tissue poised to modulate brain homeostasis and neuroinflammation. This emerging concept may be highly relevant to injuries that directly impact the skull such as in traumatic brain injury (TBI). From mild concussion to severe contusion with skull fracturing, the bone marrow response of this local myeloid cell reservoir has the potential to impact not just the acute inflammatory response in the brain, but also the remodeling of the calvarium itself, influencing its response to future head impacts. If we borrow understanding from recent discoveries in other CNS immunological niches and extend them to this nascent, but growing, subfield of neuroimmunology, it is not unreasonable to consider the hematopoietic compartment in the skull may similarly play an important role in health, aging, and neurodegenerative disease following TBI. This literature review briefly summarizes the traditional role of the skull in TBI and offers some additional insights into skull-brain interactions and their potential role in affecting secondary neuroinflammation and injury outcomes.
Topics: Humans; Brain Injuries, Traumatic; Animals; Brain; Skull; Neuroinflammatory Diseases; Bone Marrow
PubMed: 38680490
DOI: 10.3389/fimmu.2024.1353513 -
Cell Reports May 2024The traditional view of hematopoiesis is that myeloid cells derive from a common myeloid progenitor (CMP), whereas all lymphoid cell populations, including B, T, and...
The traditional view of hematopoiesis is that myeloid cells derive from a common myeloid progenitor (CMP), whereas all lymphoid cell populations, including B, T, and natural killer (NK) cells and possibly plasmacytoid dendritic cells (pDCs), arise from a common lymphoid progenitor (CLP). In Max41 transgenic mice, nearly all B cells seem to be diverted into the granulocyte lineage. Here, we show that these mice have an excess of myeloid progenitors, but their CLP compartment is ablated, and they have few pDCs. Nevertheless, T cell and NK cell development proceeds relatively normally. These hematopoietic abnormalities result from aberrant expression of Gata6 due to serendipitous insertion of the transgene enhancer (Eμ) in its proximity. Gata6 mis-expression in Max41 transgenic progenitors promoted the gene-regulatory networks that drive myelopoiesis through increasing expression of key transcription factors, including PU.1 and C/EBPa. Thus, mis-expression of a single key regulator like GATA6 can dramatically re-program multiple aspects of hematopoiesis.
Topics: GATA6 Transcription Factor; Animals; Hematopoiesis; Mice; Mice, Transgenic; Cell Lineage; Killer Cells, Natural; Mice, Inbred C57BL; Dendritic Cells; Cell Differentiation; T-Lymphocytes; Proto-Oncogene Proteins; Trans-Activators
PubMed: 38676923
DOI: 10.1016/j.celrep.2024.114159