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Cell Cycle (Georgetown, Tex.) Sep 2012The BTB-ZF (broad-complex, tramtrack and bric-à-brac--zinc finger) proteins are encoded by at least 49 genes in mouse and man and commonly serve as sequence-specific... (Review)
Review
The BTB-ZF (broad-complex, tramtrack and bric-à-brac--zinc finger) proteins are encoded by at least 49 genes in mouse and man and commonly serve as sequence-specific silencers of gene expression. This review will focus on the known physiological functions of mammalian BTB-ZF proteins, which include essential roles in the development of the immune system. We discuss their function in terminally differentiated lymphocytes and the progenitors that give rise to them, their action in hematopoietic malignancy and roles beyond the immune system.
Topics: Animals; Hematologic Neoplasms; Humans; Immunity; Lymphopoiesis; Models, Biological; Transcription Factors; Zinc Fingers
PubMed: 22894929
DOI: 10.4161/cc.21277 -
Cells Apr 2021Our understanding of the relationship between the immune system and cancers has undergone significant discovery recently. Immunotherapy with T cell therapies and... (Review)
Review
Our understanding of the relationship between the immune system and cancers has undergone significant discovery recently. Immunotherapy with T cell therapies and checkpoint blockade has meaningfully changed the oncology landscape. While remarkable clinical advances in adaptive immunity are occurring, modulation of innate immunity has proven more difficult. The myeloid compartment, including macrophages, neutrophils, and dendritic cells, has a significant impact on the persistence or elimination of tumors. Myeloid cells, specifically in the tumor microenvironment, have direct contact with tumor tissue and coordinate with tumor-reactive T cells to either stimulate or antagonize cancer immunity. However, the myeloid compartment comprises a broad array of cells in various stages of development. In addition, hematopoietic stem and progenitor cells at various stages of myelopoiesis in distant sites undergo significant modulation by tumors. Understanding how tumors exert their influence on myeloid progenitors is critical to making clinically meaningful improvements in these pathways. Therefore, this review will cover recent developments in our understanding of how solid tumors modulate myelopoiesis to promote the formation of pro-tumor immature myeloid cells. Then, it will cover some of the potential avenues for capitalizing on these mechanisms to generate antitumor immunity.
Topics: Animals; Hematopoietic Stem Cells; Humans; Immunologic Factors; Immunotherapy; Myeloid Cells; Myelopoiesis; Neoplasms; Tumor Microenvironment
PubMed: 33919157
DOI: 10.3390/cells10050968 -
Frontiers in Immunology 2019Post-transcriptional gene regulation through microRNA (miRNA) has emerged as a major control mechanism of multiple biological processes, including development and... (Review)
Review
Post-transcriptional gene regulation through microRNA (miRNA) has emerged as a major control mechanism of multiple biological processes, including development and function of T cells. T cells are vital components of the immune system, with conventional T cells playing a central role in adaptive immunity and unconventional T cells having additional functions reminiscent of both innate and adaptive immunity, such as involvement in stress responses and tissue homeostasis. Unconventional T cells encompass cells expressing semi-invariant T cell receptors (TCRs), such as invariant Natural Killer T (iNKT) and Mucosal-Associated Invariant T (MAIT) cells. Additionally, some T cells with diverse TCR repertoires, including γδT cells, intraepithelial lymphocytes (IEL) and regulatory T (Treg) cells, share some functional and/or developmental features with their semi-invariant unconventional counterparts. Unconventional T cells are particularly sensitive to disruption of miRNA function, both globally and on the individual miRNA level. Here, we review the role of miRNA in the development and function of unconventional T cells from an iNKT-centric point of view. The function of single miRNAs can provide important insights into shared and individual pathways for the formation of different unconventional T cell subsets.
Topics: Animals; Humans; Lymphopoiesis; MicroRNAs; T-Lymphocyte Subsets
PubMed: 31708931
DOI: 10.3389/fimmu.2019.02520 -
Current Opinion in Hematology Jan 2016During severe systemic infection, steady-state hematopoiesis is switched to demand-adapted myelopoiesis, leading to increased myeloid progenitor proliferation and,... (Review)
Review
PURPOSE OF REVIEW
During severe systemic infection, steady-state hematopoiesis is switched to demand-adapted myelopoiesis, leading to increased myeloid progenitor proliferation and, depending on the context and type of pathogen, enhanced granulocytic or monocytic differentiation, respectively. We will review the recent advances in understanding direct and indirect mechanisms by which different pathogen signals are detected and subsequently translated into demand-adapted myelopoiesis.
RECENT FINDINGS
Enhanced myeloid progenitor proliferation and neutrophil differentiation following infection with prototypic Gram-negative bacterium Escherichia coli is mediated by granulocyte colony-stimulating factor, and reactive oxygen species released from endothelial cells and mature myeloid cells, respectively. Furthermore, hematopoietic stem and progenitor cells directly sense pathogen signals via Toll-like receptors and contribute to emergency granulopoiesis via release and subsequent autocrine and paracrine action of myelopoietic cytokines including IL-6. Moreover, emergency monocytopoiesis upon viral infection depends on T cell-derived IFNγ and release of IL-6 from bone marrow stromal cells.
SUMMARY
A complex picture is evolving in which various hematopoietic and nonhematopoietic cell types interact with the hematopoietic system in an intricate manner to shape an appropriate hematopoietic response to specific infectious stimuli.
Topics: Adaptation, Physiological; Animals; Hematopoiesis; Hematopoietic Stem Cells; Host-Pathogen Interactions; Humans; Mesenchymal Stem Cells; Myelopoiesis; Signal Transduction
PubMed: 26554891
DOI: 10.1097/MOH.0000000000000201 -
Frontiers in Immunology 2018CD9 belongs to the tetraspanin superfamily. Depending on the cell type and associated molecules, CD9 has a wide variety of biological activities such as cell adhesion,... (Review)
Review
CD9 belongs to the tetraspanin superfamily. Depending on the cell type and associated molecules, CD9 has a wide variety of biological activities such as cell adhesion, motility, metastasis, growth, signal transduction, differentiation, and sperm-egg fusion. This review focuses on CD9 expression by hematopoietic cells and its role in modulating cellular processes involved in the regulation of inflammation. CD9 is functionally very important in many diseases and is involved either in the regulation or in the mediation of the disease. The role of CD9 in various diseases, such as viral and bacterial infections, cancer and chronic lung allograft dysfunction, is discussed. This review focuses also on its interest as a biomarker in diseases. Indeed CD9 is primarily known as a specific exosome marker however, its expression is now recognized as an anti-inflammatory marker of monocytes and macrophages. It was also described as a marker of murine IL-10-competent Breg cells and IL-10-secreting CD9 B cells were associated with better allograft outcome in lung transplant patients, and identified as a new predictive biomarker of long-term survival. In the field of cancer, CD9 was both identified as a favorable prognostic marker or as a predictor of metastatic potential depending on cancer types. Finally, this review discusses strategies to target CD9 as a therapeutic tool. Because CD9 can have opposite effects depending on the situation, the environment and the pathology, modulating CD9 expression or blocking its effects seem to be a new promising therapeutic strategy.
Topics: Animals; Biomarkers; Cell Differentiation; Cell Lineage; Disease Susceptibility; Endothelial Cells; Hematopoietic Stem Cells; Humans; Immunomodulation; Inflammation; Lymphopoiesis; Myelopoiesis; Organ Specificity; Signal Transduction; Tetraspanin 29
PubMed: 30356731
DOI: 10.3389/fimmu.2018.02316 -
Journal of Leukocyte Biology Dec 2022Sepsis remains the single most common cause of mortality and morbidity in hospitalized patients requiring intensive care. Although earlier detection and improved... (Review)
Review
Sepsis remains the single most common cause of mortality and morbidity in hospitalized patients requiring intensive care. Although earlier detection and improved treatment bundles have reduced in-hospital mortality, long-term recovery remains dismal. Sepsis survivors who experience chronic critical illness often demonstrate persistent inflammation, immune suppression, lean tissue wasting, and physical and functional cognitive declines, which often last in excess of 1 year. Older patients and those with preexisting comorbidities may never fully recover and have increased mortality compared with individuals who restore their immunologic homeostasis. Many of these responses are shared with individuals with advanced cancer, active autoimmune diseases, chronic obstructive pulmonary disease, and chronic renal disease. Here, we propose that this resulting immunologic endotype is secondary to a persistent maladaptive reprioritization of myelopoiesis and pathologic activation of myeloid cells. Driven in part by the continuing release of endogenous alarmins from chronic organ injury and muscle wasting, as well as by secondary opportunistic infections, ongoing myelopoiesis at the expense of lymphopoiesis and erythropoiesis leads to anemia, recurring infections, and lean tissue wasting. Early recognition and intervention are required to interrupt this pathologic activation of myeloid populations.
Topics: Humans; Critical Illness; Myelopoiesis; Neoplasm Recurrence, Local; Sepsis; Survivors; Chronic Disease
PubMed: 36193662
DOI: 10.1002/JLB.4MR0922-690RR -
ELife Jun 2023Polycomb repressive complex (PRC) 1 regulates stem cell fate by mediating mono-ubiquitination of histone H2A at lysine 119. While canonical PRC1 is critical for...
Polycomb repressive complex (PRC) 1 regulates stem cell fate by mediating mono-ubiquitination of histone H2A at lysine 119. While canonical PRC1 is critical for hematopoietic stem and progenitor cell (HSPC) maintenance, the role of non-canonical PRC1 in hematopoiesis remains elusive. PRC1.1, a non-canonical PRC1, consists of PCGF1, RING1B, KDM2B, and BCOR. We recently showed that PRC1.1 insufficiency induced by the loss of PCGF1 or BCOR causes myeloid-biased hematopoiesis and promotes transformation of hematopoietic cells in mice. Here we show that PRC1.1 serves as an epigenetic switch that coordinates homeostatic and emergency hematopoiesis. PRC1.1 maintains balanced output of steady-state hematopoiesis by restricting C/EBPα-dependent precocious myeloid differentiation of HSPCs and the HOXA9- and β-catenin-driven self-renewing network in myeloid progenitors. Upon regeneration, PRC1.1 is transiently inhibited to facilitate formation of granulocyte-macrophage progenitor (GMP) clusters, thereby promoting emergency myelopoiesis. Moreover, constitutive inactivation of PRC1.1 results in unchecked expansion of GMPs and eventual transformation. Collectively, our results define PRC1.1 as a novel critical regulator of emergency myelopoiesis, dysregulation of which leads to myeloid transformation.
Topics: Animals; Mice; Polycomb Repressive Complex 1; Myelopoiesis; Histones; Cell Differentiation; Hematopoietic Stem Cells
PubMed: 37266576
DOI: 10.7554/eLife.83004 -
Immunity Feb 2019Myelopoiesis ensures the steady state of the myeloid cell compartment. Technological advances in fate mapping and genetic engineering, as well as the advent of single... (Review)
Review
Myelopoiesis ensures the steady state of the myeloid cell compartment. Technological advances in fate mapping and genetic engineering, as well as the advent of single cell RNA-sequencing, have highlighted the heterogeneity of the hematopoietic system and revealed new concepts in myeloid cell ontogeny. These technologies are also shedding light on mechanisms of myelopoiesis at homeostasis and at different phases of infection and inflammation, illustrating important feedback loops between affected tissues and the bone marrow. We review these findings here and revisit principles in myelopoiesis in light of the evolving understanding of myeloid cell ontogeny and heterogeneity. We argue for the importance of system-wide evaluation of changes in myelopoiesis and discuss how even after the resolution of inflammation, long-lasting alterations in myelopoiesis may play a role in innate immune memory or trained immunity.
Topics: Animals; Bone Marrow; Homeostasis; Humans; Immunity, Innate; Infections; Inflammation; Models, Immunological; Myeloid Cells; Myeloid Progenitor Cells; Myelopoiesis
PubMed: 30784577
DOI: 10.1016/j.immuni.2019.01.019 -
Nature Communications Sep 2023Telomerase RNA (TERC) has a noncanonical function in myelopoiesis binding to a consensus DNA binding sequence and attracting RNA polymerase II (RNA Pol II), thus...
Telomerase RNA (TERC) has a noncanonical function in myelopoiesis binding to a consensus DNA binding sequence and attracting RNA polymerase II (RNA Pol II), thus facilitating myeloid gene expression. The CR4/CR5 domain of TERC is known to play this role, since a mutation of this domain found in dyskeratosis congenita (DC) patients decreases its affinity for RNA Pol II, impairing its myelopoietic activity as a result. In this study, we report that two aptamers, short single-stranded oligonucleotides, based on the CR4/CR5 domain were able to increase myelopoiesis without affecting erythropoiesis in zebrafish. Mechanistically, the aptamers functioned as full terc; that is, they increased the expression of master myeloid genes, independently of endogenous terc, by interacting with RNA Pol II and with the terc-binding sequences of the regulatory regions of such genes, enforcing their transcription. Importantly, aptamers harboring the CR4/CR5 mutation that was found in DC patients failed to perform all these functions. The therapeutic potential of the aptamers for treating neutropenia was demonstrated in several preclinical models. The findings of this study have identified two potential therapeutic agents for DC and other neutropenic patients.
Topics: Humans; Animals; Aptamers, Nucleotide; Myelopoiesis; RNA Polymerase II; Syndrome; Zebrafish; Dyskeratosis Congenita
PubMed: 37737237
DOI: 10.1038/s41467-023-41472-7 -
Current Osteoporosis Reports Apr 2018Changes in the bone marrow microenvironment, which accompany aging and obesity, including increased marrow adiposity, can compromise hematopoiesis. Here, we review... (Review)
Review
PURPOSE OF REVIEW
Changes in the bone marrow microenvironment, which accompany aging and obesity, including increased marrow adiposity, can compromise hematopoiesis. Here, we review deleterious shifts in molecular, cellular, and tissue activity and consider the potential of exercise to slow degenerative changes associated with aging and obesity.
RECENT FINDINGS
While bone marrow hematopoietic stem cells (HSC) are increased in frequency and myeloid-biased with age, the effect of obesity on HSC proliferation and differentiation remains controversial. HSC from both aged and obese environment have reduced hematopoietic reconstitution capacity following bone marrow transplant. Increased marrow adiposity affects HSC function, causing upregulation of myelopoiesis and downregulation of lymphopoiesis. Exercise, in contrast, can reduce marrow adiposity and restore hematopoiesis. The impact of marrow adiposity on hematopoiesis is determined mainly through correlations. Mechanistic studies are needed to determine a causative relationship between marrow adiposity and declines in hematopoiesis, which could aid in developing treatments for conditions that arise from disruptions in the marrow microenvironment.
Topics: Adiposity; Aging; Bone Marrow; Cell Differentiation; Cell Proliferation; Exercise; Hematopoiesis; Hematopoietic Stem Cells; Humans; Lymphopoiesis; Myelopoiesis; Obesity
PubMed: 29476393
DOI: 10.1007/s11914-018-0424-1