The Experts below are selected from a list of 2211 Experts worldwide ranked by ideXlab platform
Daniel G. Tenen - One of the best experts on this subject based on the ideXlab platform.
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c ebpγ is dispensable for steady state and emergency Granulopoiesis
Haematologica, 2018Co-Authors: Miroslava Kardosova, Daniel G. Tenen, Polina Zjablovskaja, Petr Danek, Pavla Angelisova, Lorena Lobo Figueiredopontes, Robert S Welner, Tomas Brdicka, Sanghoon LeeAbstract:The controlled production of granulocytes must be able to fulfill different needs of the organism throughout its lifetime. The maintenance of a stable basal level of mature granulocytes is ensured by steady-state Granulopoiesis,[1][1] whereas in stress situations, such as severe infection, large
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Cyclic AMP Responsive Element Binding Proteins Are Involved in ‘Emergency ’ Granulopoiesis through the Upregulation of CCAAT/Enhancer Binding Protein b
2016Co-Authors: Hideyo Hirai, Jiro Imanishi, Sakiko Satake, Naoka Kamio, Gang Huang, Akiko Matsusue, Shinpei Ogino, Nobuhiko Kimura, Eishi Ashihara, Daniel G. TenenAbstract:In contrast to the definitive role of the transcription factor, CCAAT/Enhancer binding protein a (C/EBPa), in steady-state Granulopoiesis, previous findings have suggested that Granulopoiesis during emergency situations, such as infection, is dependent on C/EBPb. In this study, a novel lentivirus-based reporter system was developed to elucidate the molecular switch required for C/EBPb-dependency. The results demonstrated that two cyclic AMP responsive elements (CREs) in the proximal promoter region of C/EBPb were involved in the positive regulation of C/EBPb transcription during granulocyte-macrophage colony-stimulating factor (GM-CSF)–induced differentiation of bone marrow cells. In addition, the transcripts of CRE binding (CREB) family proteins were readily detected in hematopoietic stem/progenitor cells. CREB was upregulated, phosphorylated and bound to the CREs in response to GM-CSF stimulation. Retroviral transduction of a dominant negative CREB mutant reduced C/EBPb mRNA levels and significantly impaired the proliferation/differentiation of granulocyte precursors, while a constitutively active form of CREB facilitated C/EBPb transcription. These data suggest that CREB protein
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cyclic amp responsive element binding proteins are involved in emergency Granulopoiesis through the upregulation of ccaat enhancer binding protein β
PLOS ONE, 2013Co-Authors: Hideyo Hirai, Jiro Imanishi, Sakiko Satake, Naoka Kamio, Gang Huang, Akiko Matsusue, Shinpei Ogino, Nobuhiko Kimura, Eishi Ashihara, Daniel G. TenenAbstract:In contrast to the definitive role of the transcription factor, CCAAT/Enhancer binding protein α (C/EBPα), in steady-state Granulopoiesis, previous findings have suggested that Granulopoiesis during emergency situations, such as infection, is dependent on C/EBPβ. In this study, a novel lentivirus-based reporter system was developed to elucidate the molecular switch required for C/EBPβ-dependency. The results demonstrated that two cyclic AMP responsive elements (CREs) in the proximal promoter region of C/EBPβ were involved in the positive regulation of C/EBPβ transcription during granulocyte-macrophage colony-stimulating factor (GM-CSF)–induced differentiation of bone marrow cells. In addition, the transcripts of CRE binding (CREB) family proteins were readily detected in hematopoietic stem/progenitor cells. CREB was upregulated, phosphorylated and bound to the CREs in response to GM-CSF stimulation. Retroviral transduction of a dominant negative CREB mutant reduced C/EBPβ mRNA levels and significantly impaired the proliferation/differentiation of granulocyte precursors, while a constitutively active form of CREB facilitated C/EBPβ transcription. These data suggest that CREB proteins are involved in the regulation of Granulopoiesis via C/EBPβ upregulation.
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c ebpα induced microrna 30c directly targets notch1 during Granulopoiesis and is repressed in acute myeloid leukemia
Blood, 2012Co-Authors: Christiane Katzerke, Daniel G. Tenen, Vikas Madan, Dennis Gerloff, Daniela Braeuerhartmann, Jensuwe Hartmann, Alexander Arthur Wurm, Carsten Muellertidow, Susanne Schnittger, Dietger NiederwieserAbstract:Abstract 3514 The transcription factor CCAAT Enhancer Binding Protein alpha (C/EBPα) is crucial for normal Granulopoiesis and frequently disrupted in acute myeloid leukemia (AML). Mutations in the CEBPA gene are reported for about 10% of all AML. Loss of function of C/EBPα leads to a block of myeloid differentiation. MicroRNAs (miR) inhibiting translation of mRNA into protein were identified as critical players in granulocytic differentiation. We and others have already shown that C/EBPα exerts its effects by regulating miRNAs such as miR-223 and miR-34a. In a global microRNA-array we found miR-30c as a novel most important target of C/EBPα during Granulopoiesis. Wild-type C/EBPα-p42 up regulates miR-30c expression, whereas the C/EBPα-p30 mutant, found in AML, does not. Furthermore, miR-30c expression is up regulated by G-CSF during granulocytic differentiation of primary human CD34-positive progenitor cells and down regulated in various subtypes of AML. Among these, miR-30c is significantly down regulated in samples from AML with normal karyotype and CEBPA mutations compared to AML patients with CEBPA wildtype. In mice, miR-30c shows a high expression in GMP and granulocytes. An induced tissue specific knock-out of C/EBPα in mice leads to a significant suppression of miR-30c expression in bone marrow cells. A luciferase reporter assay identifies NOTCH1 as a direct target of miR-30c as evident by its binding to the 39UTR. Recent studies show that Notch1 blocks protein expression of C/EBPα-p42 by activation of Tribbles homolog 2 (Trib2). On the other hand, Proteins of Notch1 and Trib2 are down regulated by C/EBPα-p42. A block of miR-30c by locked nucleic acid (LNA) oligonucleotides prevents C/EBPα–induced downregulation of Notch1 protein expression, thus, miR-30c is necessary for C/EBPα to block NOTCH1 . In this direction, the network leads to a block of Granulopoiesis and further to leukemogenesis. Our study indicates that C/EBPα-induced miR-30c inactivates Notch1 during Granulopoiesis and is down regulated in AML. This data stress the important role of deregulated miRNA expression in leukemia and may provide novel biomarkers and therapeutic targets in AML. Disclosures: Schnittger: MLL Munich Leukemia Laboratory: Equity Ownership.
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c ebpα regulated microrna 34a targets e2f3 during Granulopoiesis and is down regulated in aml with cebpa mutations
Blood, 2010Co-Authors: John Anto Pulikkan, Viola Dengler, Philomina S Peramangalam, Carsten Mullertidow, Stefan K Bohlander, Claude Preudhomme, Soheil Meshinchi, Maximilian Christopeit, Oliver Nibourel, Daniel G. TenenAbstract:The transcription factor, CCAAT enhancer binding protein alpha (C/EBPα), is crucial for Granulopoiesis and is deregulated by various mechanisms in acute myeloid leukemia (AML). Mutations in the CEBPA gene are reported in 10% of human patients with AML. Even though the C/EBPα mutants are known to display distinct biologic function during leukemogenesis, the molecular basis for this subtype of AML remains elusive. We have recently showed the significance of deregulation of C/EBPα-regulated microRNA (miR) in AML. In this study, we report that miR-34a is a novel target of C/EBPα in Granulopoiesis. During Granulopoiesis, miR-34a targets E2F3 and blocks myeloid cell proliferation. Analysis of AML samples with CEBPA mutations revealed a lower expression of miR-34a and elevated levels of E2F3 as well as E2F1, a transcriptional target of E2F3. Manipulation of miR-34a reprograms granulocytic differentiation of AML blast cells with CEBPA mutations. These results define miR-34a as a novel therapeutic target in AML with CEBPA mutations.
Sevina Dietz - One of the best experts on this subject based on the ideXlab platform.
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Innate Immune Training of Granulopoiesis Promotes Anti-tumor Activity.
Cell, 2020Co-Authors: Ioannis Kourtzelis, Jonas Schulte-schrepping, Aikaterini Hatzioannou, Tatyana Grinenko, Eman Hagag, Anupam Sinha, Canan Has, Sevina Dietz, Lydia KalafatiAbstract:Trained innate immunity, induced via modulation of mature myeloid cells or their bone marrow progenitors, mediates sustained increased responsiveness to secondary challenges. Here, we investigated whether anti-tumor immunity can be enhanced through induction of trained immunity. Pre-treatment of mice with β-glucan, a fungal-derived prototypical agonist of trained immunity, resulted in diminished tumor growth. The anti-tumor effect of β-glucan-induced trained immunity was associated with transcriptomic and epigenetic rewiring of Granulopoiesis and neutrophil reprogramming toward an anti-tumor phenotype; this process required type I interferon signaling irrespective of adaptive immunity in the host. Adoptive transfer of neutrophils from β-glucan-trained mice to naive recipients suppressed tumor growth in the latter in a ROS-dependent manner. Moreover, the anti-tumor effect of β-glucan-induced trained Granulopoiesis was transmissible by bone marrow transplantation to recipient naive mice. Our findings identify a novel and therapeutically relevant anti-tumor facet of trained immunity involving appropriate rewiring of Granulopoiesis.
Jack B. Cowland - One of the best experts on this subject based on the ideXlab platform.
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Granulopoiesis and granules of human neutrophils.
Immunological reviews, 2016Co-Authors: Jack B. CowlandAbstract:Summary Granules are essential for the ability of neutrophils to fulfill their role in innate immunity. Granule membranes contain proteins that react to environmental cues directing neutrophils to sites of infection and initiate generation of bactericidal oxygen species. Granules are densely packed with proteins that contribute to microbial killing when liberated to the phagosome or extracellularly. Granules are, however, highly heterogeneous and are traditionally subdivided into azurophil granules, specific granules, and gelatinase granules in addition to secretory vesicles. This review will address issues pertinent to formation of granules, which is a process intimately connected to maturation of neutrophils from their precursors in the bone marrow. We further discuss possible mechanisms by which decisions are made regarding sorting of proteins to constitutive secretion or storage in granules and how degranulation of granule subsets is regulated.
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changes in gene expression during g csf induced emergency Granulopoiesis in humans
Blood, 2015Co-Authors: Corinna Cavan Pedersen, Jack B. Cowland, Rehannah Borup, Anna Fossum, Anne Fischernielsen, Helena Morajensen, Niels BorregaardAbstract:Emergency Granulopoiesis refers to the increased production of neutrophils in bone marrow and their release into circulation induced by severe infection. Several studies point to a critical role for granulocyte colony-stimulating factor (G-CSF) as the main mediator of emergency Granulopoiesis. However, the consequences of G-CSF stimulation on the transcriptome of neutrophils and their precursors have not yet been elucidated in humans. Here, we investigate the changes in mRNA and miRNA expression in successive stages of neutrophil development following in vivo administration of G-CSF in humans, mimicking emergency Granulopoiesis. Blood samples were collected from healthy individuals after five days of G-CSF administration. Neutrophil precursors were sorted into discrete stages of maturation by flow cytometry and extracted RNA was subjected to microarray analysis. mRNA levels were compared to previously published expression levels in corresponding populations of neutrophil precursors isolated from bone marrow of untreated, healthy individuals. miRNA expression was investigated in the most mature cell population to determine G-CSF-induced changes in circulating neutrophils. G-CSF substantially affected mRNA and miRNA expression patterns, demonstrating significant impact on neutrophil development and function. 1110 mRNAs were differentially expressed more than 2-fold with G-CSF while the treatment induced changes in the levels of 73 miRNAs in the mature population. In addition, G-CSF treatment reduced the levels of four out of five measured granule proteins in mature neutrophils including hCAP-18, which was completely deficient in neutrophils from G-CSF-treated donors. Cell cycle analysis pointed towards an induced proliferative capacity of myelocytes. These results indicate that multiple biological processes are altered in order to satisfy the increased demand for neutrophils during G-CSF-induced emergency Granulopoiesis. Disclosures No relevant conflicts of interest to declare.
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microrna profiling in human neutrophils during bone marrow Granulopoiesis and in vivo exudation
PLOS ONE, 2013Co-Authors: Maria Torp Larsen, Niels Borregaard, Corinna Cavan Pedersen, Kim Theilgaardmonch, Jack B. Cowland, Christoffer Hother, Mattias HagerAbstract:The purpose of this study was to describe the microRNA (miRNA) expression profiles of neutrophils and their precursors from the initiation of Granulopoiesis in the bone marrow to extravasation and accumulation in skin windows. We analyzed three different cell populations from human bone marrow, polymorphonuclear neutrophil (PMNs) from peripheral blood, and extravasated PMNs from skin windows using the Affymetrix 2.0 platform. Our data reveal 135 miRNAs differentially regulated during bone marrow Granulopoiesis. The majority is differentially regulated between the myeloblast/promyelocyte (MB/PM) and myelocyte/metamyelocyte (MC/MM) stages of development. These 135 miRNAs were divided into six clusters according to the pattern of their expression. Several miRNAs demonstrate a pronounced increase or reduction at the transition between MB/PM and MC/MM, which is associated with cell cycle arrest and the initiation of terminal differentiation. Seven miRNAs are differentially up-regulated between peripheral blood PMNs and extravasated PMNs and only one of these (miR-132) is also differentially regulated during Granulopoiesis. The study indicates that several different miRNAs participate in the regulation of normal Granulopoiesis and that miRNAs might also regulate activities of extravasated neutrophils. The data present the miRNA profiles during the development and activation of the neutrophil granulocyte in healthy humans and thus serves as a reference for further research of normal and malignant granulocytic development.
Lydia Kalafati - One of the best experts on this subject based on the ideXlab platform.
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Innate Immune Training of Granulopoiesis Promotes Anti-tumor Activity.
Cell, 2020Co-Authors: Ioannis Kourtzelis, Jonas Schulte-schrepping, Aikaterini Hatzioannou, Tatyana Grinenko, Eman Hagag, Anupam Sinha, Canan Has, Sevina Dietz, Lydia KalafatiAbstract:Trained innate immunity, induced via modulation of mature myeloid cells or their bone marrow progenitors, mediates sustained increased responsiveness to secondary challenges. Here, we investigated whether anti-tumor immunity can be enhanced through induction of trained immunity. Pre-treatment of mice with β-glucan, a fungal-derived prototypical agonist of trained immunity, resulted in diminished tumor growth. The anti-tumor effect of β-glucan-induced trained immunity was associated with transcriptomic and epigenetic rewiring of Granulopoiesis and neutrophil reprogramming toward an anti-tumor phenotype; this process required type I interferon signaling irrespective of adaptive immunity in the host. Adoptive transfer of neutrophils from β-glucan-trained mice to naive recipients suppressed tumor growth in the latter in a ROS-dependent manner. Moreover, the anti-tumor effect of β-glucan-induced trained Granulopoiesis was transmissible by bone marrow transplantation to recipient naive mice. Our findings identify a novel and therapeutically relevant anti-tumor facet of trained immunity involving appropriate rewiring of Granulopoiesis.
Garnett Kelsoe - One of the best experts on this subject based on the ideXlab platform.
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inflammation triggers emergency Granulopoiesis through a density dependent feedback mechanism
PLOS ONE, 2011Co-Authors: Derek W. Cain, Pilar Snowden, Gregory D. Sempowski, Garnett KelsoeAbstract:Normally, neutrophil pools are maintained by homeostatic mechanisms that require the transcription factor C/EBPα. Inflammation, however, induces neutrophilia through a distinct pathway of “emergency” Granulopoiesis that is dependent on C/EBPβ. Here, we show in mice that alum triggers emergency Granulopoiesis through the IL-1RI-dependent induction of G-CSF. G-CSF/G-CSF-R neutralization impairs proliferative responses of hematopoietic stem and progenitor cells (HSPC) to alum, but also abrogates the acute mobilization of BM neutrophils, raising the possibility that HSPC responses to inflammation are an indirect result of the exhaustion of BM neutrophil stores. The induction of neutropenia, via depletion with Gr-1 mAb or myeloid-specific ablation of Mcl-1, elicits G-CSF via an IL-1RI-independent pathway, stimulating granulopoietic responses indistinguishable from those induced by adjuvant. Notably, C/EBPβ, thought to be necessary for enhanced generative capacity of BM, is dispensable for increased proliferation of HSPC to alum or neutropenia, but plays a role in terminal neutrophil differentiation during granulopoietic recovery. We conclude that alum elicits a transient increase in G-CSF production via IL-1RI for the mobilization of BM neutrophils, but density-dependent feedback sustains G-CSF for accelerated Granulopoiesis.
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il 1r type i dependent hemopoietic stem cell proliferation is necessary for inflammatory Granulopoiesis and reactive neutrophilia
Journal of Immunology, 2009Co-Authors: Yoshihiro Ueda, Derek W. Cain, Garnett Kelsoe, Masayuki Kuraoka, Motonari KondoAbstract:Infections and inflammation trigger neutrophilias that are supported by a hematopoietic program of accelerated Granulopoiesis known as emergency Granulopoiesis. The intrinsic factors that drive reactive neutrophilias and emergency Granulopoiesis have been inferred but not demonstrated. Here, we show that alum cannot elicit reactive neutrophilias in IL-1R type I (IL-1RI)−/− mice, whereas other inflammatory responses, including eosinophilia and Ab production, remain intact. Analysis of this specific impairment revealed an unanticipated role for IL-1RI in supporting increased proliferation by granulocyte/macrophage progenitors and, surprisingly, multipotent progenitors and hematopoietic stem cells (HSC). Indeed, HSC and multipotent progenitor proliferative responses were most suppressed in IL-1RI−/− mice, suggesting a critical role for their proliferation in inflammatory Granulopoiesis. Whereas IL-1 drives increased HSC proliferation directly in vitro, IL-1RI expression by radiation-resistant host cells was both necessary and sufficient for alum-induced HSC, multipotent progenitor, and granulocyte/macrophage progenitor proliferation and reactive neutrophilias in radiation chimeric mice. Thus, IL-1 plays a necessary, but indirect, role in the support of alum-induced neutrophilias by expanding both pluripotent and myeloid progenitor compartments to accelerate Granulopoiesis.
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inflammation and the reciprocal production of granulocytes and lymphocytes in bone marrow
Journal of Experimental Medicine, 2005Co-Authors: Yoshihiro Ueda, Motonari Kondo, Garnett KelsoeAbstract:The coordinated production of leukocytes in bone marrow is crucial for innate and adaptive immunity. Inflammation alters normal leukocyte production by promoting Granulopoiesis over lymphopoiesis, a response that supports the reactive neutrophilia that follows infection. Here we demonstrate that this specialization for Granulopoiesis is determined by inflammation-induced reductions of growth and retention factors, most significantly stem cell factor and CXCL12, which act preferentially to inhibit lymphoid development. These hierarchical effects suggest that the normal equilibrium of leukocyte production in bone marrow is determined by lymphopoiesis' higher demand for specific growth factors and/or retention signals. Inflammation regulates this balance by reducing growth factors that have less impact on developing neutrophils than lymphocytes. We demonstrate that Granulopoiesis and lymphopoiesis are coupled specifically in the bone marrow by development in a common niche and propose that the leukopoietic equilibrium is specified by limiting amounts of developmental resources.
