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Current Opinion in Hematology Jan 2017Eosinophils are a subset of granulocytes generally associated with type 2 immune responses. They can contribute to protection against helminths but also mediate... (Review)
Review
PURPOSE OF REVIEW
Eosinophils are a subset of granulocytes generally associated with type 2 immune responses. They can contribute to protection against helminths but also mediate pro-inflammatory functions during allergic immune responses. Only recently, eosinophils were also found to exert many other functions such as regulation of glucose and fat metabolism, thermogenesis, survival of plasma cells, and antitumor activity. The mechanisms that control eosinophil development and survival are only partially understood.
RECENT FINDINGS
Here we review new findings regarding the role of cell-extrinsic and cell-intrinsic factors for eosinophilopoiesis and eosinophil homeostasis. Several reports provide new insights in the regulation of eosinophil development by transcription factors, miRNAs and epigenetic modifications. Danger signals like lipopolysaccharide or alarmins can activate eosinophils but also prolong their lifespan. We further reflect on the observations that eosinophil development is tightly controlled by the unfolded protein stress response and formation of cytoplasmic granules.
SUMMARY
Eosinophils emerge as important regulators of diverse biological processes. Their differentiation and survival is tightly regulated by factors that are still poorly understood. Newly identified pathways involved in eosinophilopoiesis and eosinophil homeostasis may lead to development of new therapeutic options for treatment of eosinophil-associated diseases.
Topics: Alarmins; Animals; Antigens, Differentiation, Myelomonocytic; Bone Marrow; Cell Differentiation; Cell Survival; Eosinophils; Gene Expression Regulation; Granulocyte Precursor Cells; Homeostasis; Humans; Interleukin-5; Leukopoiesis; MicroRNAs; Protein Binding; Signal Transduction; Transcription Factors
PubMed: 27673511
DOI: 10.1097/MOH.0000000000000293 -
Leukemia Sep 2023The transcription factor CCAAT-enhancer binding factor alpha (C/ebpα) is a master controller of myeloid differentiation that is expressed as long (p42) and short (p30)...
The transcription factor CCAAT-enhancer binding factor alpha (C/ebpα) is a master controller of myeloid differentiation that is expressed as long (p42) and short (p30) isoform. Mutations within the CEBPA gene selectively deleting p42 are frequent in human acute myeloid leukemia. Here we investigated the individual genomics and transcriptomics of p42 and p30. Both proteins bound to identical sites across the genome. For most targets, they induced a highly similar transcriptional response with the exception of a few isoform specific genes. Amongst those we identified early growth response 1 (Egr1) and tribbles1 (Trib1) as key targets selectively induced by p42 that are also underrepresented in CEBPA-mutated AML. Egr1 executed a program of myeloid differentiation and growth arrest. Oppositely, Trib1 established a negative feedback loop through activation of Erk1/2 kinase thus placing differentiation under control of signaling. Unexpectedly, differentiation elicited either by removal of an oncogenic input or by G-CSF did not peruse C/ebpα as mediator but rather directly affected the cell cycle core by upregulation of p21/p27 inhibitors. This points to functions downstream of C/ebpα as intersection point where transforming and differentiation stimuli converge and this finding offers a new perspective for therapeutic intervention.
Topics: Humans; Granulocyte Precursor Cells; Leukemia, Myeloid, Acute; Cell Differentiation; Protein Isoforms; Mutation; CCAAT-Enhancer-Binding Protein-alpha
PubMed: 37532789
DOI: 10.1038/s41375-023-01989-8 -
Blood Dec 2017
Topics: Adult; Back Pain; Fatal Outcome; Female; Granulocyte Precursor Cells; Humans; Immunophenotyping; Leukemia, Mast-Cell; Leukemia, Promyelocytic, Acute; Neoplastic Cells, Circulating
PubMed: 29242209
DOI: 10.1182/blood-2017-08-803346 -
Seminars in Fetal & Neonatal Medicine Aug 2007The growth factors erythropoietin and granulocyte-colony stimulating factor have hematopoietic and non-hematopoietic functions. Both are used clinically in their... (Review)
Review
The growth factors erythropoietin and granulocyte-colony stimulating factor have hematopoietic and non-hematopoietic functions. Both are used clinically in their recombinant forms. Both also have interesting tissue-protective effects in other organs, which are unrelated to their hematopoietic functions. They have clinical hematopoietic uses in neonatal populations and in experimental non-hematopoietic research, and clinical potential as neuroprotective or tissue-protective agents.
Topics: Animals; Central Nervous System; Clinical Trials as Topic; Erythroid Precursor Cells; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte Precursor Cells; Humans; Neuroprotective Agents; Recombinant Proteins
PubMed: 17321813
DOI: 10.1016/j.siny.2007.01.015 -
Haematologica Aug 2015Acute promyelocytic leukemia is an aggressive malignancy characterized by the accumulation of promyelocytes in the bone marrow. PML/RARA is the primary abnormality...
Acute promyelocytic leukemia is an aggressive malignancy characterized by the accumulation of promyelocytes in the bone marrow. PML/RARA is the primary abnormality implicated in this pathology, but the mechanisms by which this chimeric fusion protein initiates disease are incompletely understood. Identifying PML/RARA targets in vivo is critical for comprehending the road to pathogenesis. Utilizing a novel sorting strategy, we isolated highly purified promyelocyte populations from normal and young preleukemic animals, carried out microarray and methylation profiling analyses, and compared the results from the two groups of animals. Surprisingly, in the absence of secondary lesions, PML/RARA had an overall limited impact on both the transcriptome and methylome. Of interest, we did identify down-regulation of secondary and tertiary granule genes as the first step engaging the myeloid maturation block. Although initially not sufficient to arrest terminal granulopoiesis in vivo, such alterations set the stage for the later, complete differentiation block seen in leukemia. Further, gene set enrichment analysis revealed that PML/RARA promyelocytes exhibit a subtle increase in expression of cell cycle genes, and we show that this leads to both increased proliferation of these cells and expansion of the promyelocyte compartment. Importantly, this proliferation signature was absent from the poorly leukemogenic p50/RARA fusion model, implying a critical role for PML in the altered cell-cycle kinetics and ability to initiate leukemia. Thus, our findings challenge the predominant model in the field and we propose that PML/RARA initiates leukemia by subtly shifting cell fate decisions within the promyelocyte compartment.
Topics: Animals; Antigens, CD34; Cell Proliferation; Cell Transformation, Neoplastic; Cluster Analysis; DNA Methylation; Disease Models, Animal; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Granulocyte Precursor Cells; Humans; Immunophenotyping; Leukemia, Promyelocytic, Acute; Mice; Mice, Transgenic; Neoplastic Stem Cells; Oncogene Proteins, Fusion; Transcription, Genetic
PubMed: 26088929
DOI: 10.3324/haematol.2014.123018 -
Biological Chemistry Oct 2014Angiotensin-converting enzyme (ACE) plays an important role in blood pressure control. ACE also has effects on renal function, reproduction, hematopoiesis, and several... (Review)
Review
Angiotensin-converting enzyme (ACE) plays an important role in blood pressure control. ACE also has effects on renal function, reproduction, hematopoiesis, and several aspects of the immune response. ACE 10/10 mice overexpress ACE in monocytic cells; macrophages from ACE 10/10 mice demonstrate increased polarization toward a proinflammatory phenotype. As a result, ACE 10/10 mice have a highly effective immune response following challenge with melanoma, bacterial infection, or Alzheimer disease. As shown in ACE 10/10 mice, enhanced monocytic function greatly contributes to the ability of the immune response to defend against a wide variety of antigenic and non-antigenic challenges.
Topics: Animals; Granulocyte Precursor Cells; Immunity, Cellular; Mice; Mice, Knockout; Peptidyl-Dipeptidase A
PubMed: 24633750
DOI: 10.1515/hsz-2013-0295 -
Blood Nov 2018
Topics: Aged; Cell Count; Crystallization; Granulocyte Precursor Cells; Humans; Inclusion Bodies; Male; Multiple Myeloma; Plasma Cells
PubMed: 30385493
DOI: 10.1182/blood-2018-08-868968 -
Blood Mar 2021
Topics: Blood Cell Count; Child; Erythrocytes; Female; Granulocyte Precursor Cells; Humans; Leukemia, Myeloid, Acute
PubMed: 33734334
DOI: 10.1182/blood.2020009744 -
Chest Nov 2008Asthma, allergic rhinitis, nasal polyposis, chronic rhinosinusitis, and related forms of upper and lower airway diseases are often characterized by eosinophilic and... (Review)
Review
Asthma, allergic rhinitis, nasal polyposis, chronic rhinosinusitis, and related forms of upper and lower airway diseases are often characterized by eosinophilic and basophilic inflammation, involving systemic processes. Eosinophil/basophil (Eo/B) lineage-committed progenitor cells in cord blood, peripheral blood, bone marrow, lung tissue, and sputum are up-regulated in the above conditions, and respond to allergen and other stimuli with increased differentiative and migratory capacity. A considerable body of evidence now exists showing that activation of such Eo/B-selective hemopoietic processes is not only associated with the onset and maintenance of allergic inflammation in atopic adults, but also with the development of the allergic diathesis. Moreover, eosinophilopoietic processes within hemopoietic compartments and, importantly, at mucosal tissue sites during an allergic inflammatory response provide novel targets for the treatment of allergy as a systemic process and disease.
Topics: Animals; Eosinophils; Granulocyte Precursor Cells; Humans; Immunity, Cellular; Respiratory Tract Diseases
PubMed: 18988778
DOI: 10.1378/chest.08-0485 -
Oncogene Nov 2009MicroRNAs (miRNAs) are small non-coding RNAs involved in the regulation of critical cell processes such as apoptosis, cell proliferation and differentiation. A small set...
MicroRNAs (miRNAs) are small non-coding RNAs involved in the regulation of critical cell processes such as apoptosis, cell proliferation and differentiation. A small set of miRNAs is differentially expressed in hematopoietic cells and seemingly has an important role in granulopoiesis and lineage differentiation. In this study, we analysed, using a quantitative real-time PCR approach, the expression of 12 granulocytic differentiation signature miRNAs in a cohort of acute promyelocytic leukemia (APL) patients. We found nine miRNAs overexpressed and three miRNAs (miR-107, -342 and let-7c) downregulated in APL blasts as compared with normal promyelocytes differentiated in vitro from CD34+ progenitors. Patients successfully treated with all-trans-retinoic acid (ATRA) and chemotherapy showed downregulation of miR-181b and upregulation of miR-15b, -16, -107, -223, -342 and let-7c. We further investigated whether the APL-associated oncogene, promyelocytic leukemia gene (PML)/retinoic acid receptor alpha (RARalpha), might be involved in the transcriptional repression of miR-107, -342 and let-7c. We found that PML/RARalpha binds the regulatory sequences of the intragenic miR-342 and let-7c. In addition, we observed, in response to ATRA, the release of PML/RARalpha paralleled by their transcriptional activation, together with their host genes, EVL and C21orf34alpha. In conclusion, we show that a small subset of miRNAs is differentially expressed in APL and modulated by ATRA-based treatment.
Topics: Granulocyte Precursor Cells; Humans; Leukemia, Promyelocytic, Acute; MicroRNAs
PubMed: 19749800
DOI: 10.1038/onc.2009.255