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Shengjun Wang - One of the best experts on this subject based on the ideXlab platform.
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Interferon regulatory factor 8 governs Myeloid Cell Development.
Cytokine & Growth Factor Reviews, 2020Co-Authors: Xueli Xia, Wenxin Wang, Kai Yin, Shengjun WangAbstract:Interferon regulatory factors (IRFs) are a family of central transcriptional regulators that produce type I interferon and regulate innate and adaptive immune responses. Interferon regulatory factor 8 (IRF8) exists mainly in hematopoietic Cells and is essential for the Development of several Myeloid lineages, including monocytes/macrophages and dendritic Cells. In recent years, an increasing number of studies have focused on the roles of IRF8 in the differentiation of Myeloid pedigree and MDSC aggregation in diseases such as tumors. In this review, we provide a comprehensive overview of the roles of IRF8 in the regulation of Myeloid Cell Development, with particular reference to multiple disease conditions. Clarifying the various functions of IRF8 may suggest targets for therapeutic interventions.
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Long Non-Coding RNA HOXA Transcript Antisense RNA Myeloid-Specific 1-HOXA1 Axis Downregulates the Immunosuppressive Activity of Myeloid-Derived Suppressor Cells in Lung Cancer.
Frontiers in Immunology, 2018Co-Authors: Xinyu Tian, Shengjun Wang, Ting Wang, Jie Tian, Yue Zhang, Lingxiang MaoAbstract:HOXA transcript antisense RNA Myeloid-specific 1 (HOTAIRM1) is a long non-coding RNA that has been shown to be a key regulator of Myeloid Cell Development by targeting HOXA1. Myeloid-derived suppressor Cells (MDSCs) are a heterogeneous population of immature Myeloid Cells that possess immunosuppressive function. However, the impact of HOTAIRM1 on the Development of MDSCs remains unknown. In this study, we demonstrated that HOTAIRM1 was expressed in MDSCs and that over-expression of HOTAIRM1 could down-regulate the expression of suppressive molecules in MDSCs. In addition, HOTAIRM1 levels were observed to be decreased in the peripheral blood Cells of lung cancer patients compared to those of healthy controls. By analysing HOTAIRM1 expression levels in different types of lung cancer, we found that HOTAIRM1 was mainly expressed in lung adenocarcinoma. Finally, it was confirmed that HOTAIRM1 could enhance the expression of HOXA1 in MDSCs and that high levels of HOXA1, the target gene of HOTAIRM1, could delay tumour progression and enhance the anti-tumour immune response by down-regulating the immunosuppression of MDSCs. Taken together, the present study illustrates that HOTAIRM1/HOXA1 down-regulates the immunosuppressive function of MDSCs and may be a potential therapeutic target in lung cancer.
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long non coding rna hoxa transcript antisense rna Myeloid specific 1 hoxa1 axis downregulates the immunosuppressive activity of Myeloid derived suppressor Cells in lung cancer
Frontiers in Immunology, 2018Co-Authors: Xinyu Tian, Ting Wang, Jie Tian, Yue Zhang, Lingxiang Mao, Shengjun WangAbstract:HOXA transcript antisense RNA Myeloid-specific 1 (HOTAIRM1) is a long non-coding RNA that has been shown to be a key regulator of Myeloid Cell Development by targeting HOXA1. Myeloid-derived suppressor Cells (MDSCs) are a heterogeneous population of immature Myeloid Cells that possess immunosuppressive function. However, the impact of HOTAIRM1 on the Development of MDSCs remains unknown. In this study, we demonstrated that HOTAIRM1 was expressed in MDSCs and that overexpression of HOTAIRM1 could downregulate the expression of suppressive molecules in MDSCs. In addition, HOTAIRM1 levels were observed to be decreased in the peripheral blood Cells of lung cancer patients compared with those of healthy controls. By analyzing HOTAIRM1 expression levels in different types of lung cancer, we found that HOTAIRM1 was mainly expressed in lung adenocarcinoma. Finally, it was confirmed that HOTAIRM1 could enhance the expression of HOXA1 in MDSCs and that high levels of HOXA1, the target gene of HOTAIRM1, could delay tumor progression and enhance the antitumor immune response by downregulating the immunosuppression of MDSCs. Taken together, this study illustrates that HOTAIRM1/HOXA1 downregulates the immunosuppressive function of MDSCs and may be a potential therapeutic target in lung cancer.
Tomohiko Tamura - One of the best experts on this subject based on the ideXlab platform.
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1024 - EPIGENETIC CONTROL OF Myeloid Cell Development BY THE TRANSCRIPTION FACTOR IRF8
Experimental Hematology, 2019Co-Authors: Tomohiko TamuraAbstract:Differentiation of hematopoietic stem and progenitor Cells to various types of blood Cells is a process of establishing Cell type-specific gene expression patterns. We have been investigating the mechanism of Myeloid Cell Development from a viewpoint of gene expression control by transcription factors, particularly IRF8. In Irf8–/– mice, mononuclear phagocyte progenitors are accumulated, and these progenitors do not efficiently differentiate into monocytes (Mos) or dendritic Cells (DCs) but instead, give rise to a large number of neutrophils. Accordingly, the loss of IRF8 causes immunodeficiency and chronic Myeloid leukemia-like neutrophilia in mice and humans. Recently, we found that a novel 3’ enhancer is responsible for high Irf8 expression in the DC lineage. Deletion of this enhancer in vivo resulted in the loss of classical DC1s (cDC1s) and somehow surprisingly, caused a significant increase in Mo counts. Thus, the expression level of IRF8 determines the fate of Myeloid progenitors; absence, low, or high expression of IRF8 promotes differentiation towards neutrophils, Mos, or DCs, respectively. We also analyzed enhancer landscape dynamics and the genome-wide behavior of IRF8 during the Development of mononuclear phagocytes in vivo. While IRF8 does not immediately change the global gene expression pattern in the mononuclear phagocyte progenitors, it does establish their enhancer landscapes by cooperating or antagonizing with other transcription factors, thereby preparing for future gene expression. Furthermore, we found that IRF8 is weakly expressed in a subpopulation of lymphoid-primed multipotent progenitors and leads to early lineage specification towards cDC1s by regulating chromatin states before inducing major transcriptional changes. We are now investigating the 3D chromatin structure dynamics and the role of IRF8 during Myeloid Development. Collectively, these results illustrate that the epigenetic changes induced by key transcription factors such as IRF8 determine the fate of hematopoietic progenitor Cells before establishing gene expression patterns.
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Guest editorial: Transcriptional control in Myeloid Cell Development and related diseases.
International Journal of Hematology, 2015Co-Authors: Tomohiko TamuraAbstract:four review articles focusing on the biology of these important transcriptional regulators. Rapid advances in recent years in high-throughput experimental techniques, including microarrays, next-generation sequencing (such as chromatin immunoprecipitation sequencing and RNA sequencing), and high-sensitivity mass spectrometry, as well as Developments in bioinformatics, have ushered in a new era in the study of transcriptional control. Comprehensive gene expression profiles and even the precise locations of transcription regulator binding and chromatin modifications throughout the genome can now be obtained. Systematic identification of the components of large protein complexes is also now achievable. Using such techniques, research into transcriptional control in Myeloid Cell Development and related diseases has produced major advances in recent years. In the first of the four reviews, Bonifer and colleagues provide an update on the Developmental stage-specific function of RUNX1 and its important target, PU.1, during myelopoiesis from both Cellular and molecular aspects. They also describe the close relationship between these two critical factors, which show reciprocal regulation of gene expression and synergistic function. Moreover, these authors summarize the known mutations and translocations involving RUNX1 or PU.1, as well as the ‘addiction’ to naive RUNX1 and PU.1 in the Development of acute Myeloid leukemia (AML) [1]. Friedman describes the molecular basis of how C/ EBPα activates transcription as a homodimer and through its interactions with other bZIP transcription factors, such as AP-1, during myelopoiesis. The role of C/EBPα in the Development of Myeloid Cells, particularly granulocytes and monocytes, and in the regulation of the Cell cycle, survival, and quiescence, is highlighted. Moreover, Friedman summarizes the known mutations in CEBPA, the The diverse Cell types of the body exhibit distinct morphologies and functions, despite the fact that (with the exception of antigen receptor genes in lymphocytes) the genome sequence is essentially identical among all Cell types in an individual. The molecular basis for this diversity is that among the approximately 22,000 genes encoded by the human genome, only a specific set is expressed in a given Cell type. The differentiation of stem or progenitor Cells to mature Cells is a sequential process of activation, inactivation, or maintenance of the selected genes—i.e., transcriptional control—that ultimately determines Cell fate. Numerous studies have shown that transcription factors and epigenetic regulators play essential roles in Cell differentiation. Dysregulation of these processes can result in various diseases, including cancers, such as leukemias in the case of hematopoiesis. Myeloid Cells, e.g., granulocytes, monocytes/macrophages, dendritic Cells, and mast Cells, are generated from hematopoietic stem Cells in the bone marrow via multipotent progenitors, common Myeloid progenitors, granulocyte–monocyte progenitors, and more committed progenitors. Multiple factors have been identified as essential for the regulation of myelopoiesis. These include the transcription factors runt-related transcription factor 1 (RUNX1), PU.1, CCAAT/enhancer binding proteins (C/ EBPs), and interferon regulatory factor-8 (IRF8), and the chromatin regulator mixed-lineage leukemia (MLL). In this issue of International Journal of Hematology, we present Transcriptional control in Myeloid Cell Development and related diseases
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Identification of target genes and a unique cis element regulated by IRF-8 in developing macrophages
Blood, 2005Co-Authors: Tomohiko Tamura, Pratima Thotakura, Tetsuya S. Tanaka, Keiko OzatoAbstract:Interferon regulatory factor-8 (IRF-8)/interferon consensus sequence–binding protein (ICSBP) is a transcription factor that controls Myeloid-Cell Development. Microarray gene expression analysis of Irf-8-/- Myeloid progenitor Cells expressing an IRF-8/estrogen receptor chimera (which differentiate into macrophages after addition of estradiol) was used to identify 69 genes altered by IRF-8 during early differentiation (62 up-regulated and 7 down-regulated). Among them, 4 lysosomal/endosomal enzyme-related genes (cystatin C, cathepsin C, lysozyme, and prosaposin) did not require de novo protein synthesis for induction, suggesting that they were direct targets of IRF-8. We developed a reporter assay system employing a self-inactivating retrovirus and analyzed the cystatin C and cathepsin C promoters. We found that a unique cis element mediates IRF-8–induced activation of both promoters. Similar elements were also found in other IRF-8 target genes with a consensus sequence (GAAANN[N]GGAA) comprising a core IRF-binding motif and an Ets-binding motif; this sequence is similar but distinct from the previously reported Ets/IRF composite element. Chromatin immunoprecipitation assays demonstrated that IRF-8 and the PU.1 Ets transcription factor bind to this element in vivo. Collectively, these data indicate that IRF-8 stimulates transcription of target genes through a novel cis element to specify macrophage differentiation.
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ICSBP/IRF-8 inhibits mitogenic activity of p210 Bcr/Abl in differentiating Myeloid progenitor Cells
Blood, 2003Co-Authors: Tomohiko Tamura, Hideki Tsujimura, Keiko Ozato, Hee Jeong Kong, Chainarong Tunyaplin, Kathryn CalameAbstract:Interferon consensus sequence binding protein/interferon regulatory factor 8 (ICSBP/IRF-8) is a transcription factor that controls Myeloid Cell Development. ICSBP-/- mice develop a chronic myelogenous leukemia (CML)-like syndrome. Several observations on patients and mouse models have implicated ICSBP in the pathogenesis of CML. In this paper, we investigated whether ICSBP modulates the growth-promoting activity of Bcr/Abl, the causal oncoprotein for CML. When transformed with p210 Bcr/Abl, ICSBP-/- Myeloid progenitor Cells lost growth factor dependence and grew in the absence of granulocyte-macrophage colony-stimulating factor. When ICSBP was ectopically expressed, Bcr/Abl-transformed Cells underwent complete growth arrest and differentiated into mature, functional macrophages without inhibiting the kinase activity of Bcr/Abl. Providing a mechanistic basis for the growth arrest, ICSBP markedly repressed c-Myc messenger RNA (mRNA)-expression, a downstream target of Bcr/Abl. A further analysis with the ICSBP/estrogen receptor chimera showed that ICSBP repression of c-Myc is indirect and is mediated by another gene(s). We identified Blimp-1 and METS/PE1, potent c-Myc repressors, as direct targets of ICSBP activated in these Cells. Consistent with this, ectopic Blimp-1 repressed c-Myc expression and inhibited Cell growth. These results indicate that ICSBP inhibits growth of Bcr/Abl-transformed Myeloid progenitor Cells by activating several genes that interfere with the c-Myc pathway.
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ifn consensus sequence binding protein ifn regulatory factor 8 guides bone marrow progenitor Cells toward the macrophage lineage
Journal of Immunology, 2002Co-Authors: Hideki Tsujimura, Tomohiko Tamura, Tokiko Nagamurainoue, Keiko OzatoAbstract:IFN consensus sequence binding protein (ICSBP; IFN regulatory factor-8) is a transcription factor of the IFN regulatory factor family. Disruption of this gene results in a leukemia-like disease in mice. To investigate the role of ICSBP in Myeloid Cell Development, lineage marker-negative (Lin−) bone marrow progenitor Cells were purified from ICSBP+/+ and ICSBP−/− mice and tested for gene expression and colony-forming ability. ICSBP was expressed in Lin− progenitor Cells, and its levels were markedly increased by IFN-γ. The colony-forming potential of ICSBP−/− progenitor Cells was grossly abnormal, as they gave rise to a disproportionately high number of granulocyte colonies and many fewer macrophage colonies. IFN-γ inhibited colony formation, while promoting macrophage maturation in ICSBP+/+ Cells. In contrast, the effects of IFN-γ were completely absent in ICSBP−/− progenitors. By retrovirus transduction we tested whether reintroduction of ICSBP restores a normal colony-forming potential in −/− progenitor Cells. The wild-type ICSBP, but not transcriptionally defective mutants, corrected abnormal colony formation by increasing macrophage colonies and decreasing granulocyte colonies. Taken together, ICSBP plays a critical role in Myeloid Cell Development by controlling lineage selection and is indispensable for IFN-γ-dependent modulation of progenitor Cell maturation.
Keiko Ozato - One of the best experts on this subject based on the ideXlab platform.
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Identification of target genes and a unique cis element regulated by IRF-8 in developing macrophages
Blood, 2005Co-Authors: Tomohiko Tamura, Pratima Thotakura, Tetsuya S. Tanaka, Keiko OzatoAbstract:Interferon regulatory factor-8 (IRF-8)/interferon consensus sequence–binding protein (ICSBP) is a transcription factor that controls Myeloid-Cell Development. Microarray gene expression analysis of Irf-8-/- Myeloid progenitor Cells expressing an IRF-8/estrogen receptor chimera (which differentiate into macrophages after addition of estradiol) was used to identify 69 genes altered by IRF-8 during early differentiation (62 up-regulated and 7 down-regulated). Among them, 4 lysosomal/endosomal enzyme-related genes (cystatin C, cathepsin C, lysozyme, and prosaposin) did not require de novo protein synthesis for induction, suggesting that they were direct targets of IRF-8. We developed a reporter assay system employing a self-inactivating retrovirus and analyzed the cystatin C and cathepsin C promoters. We found that a unique cis element mediates IRF-8–induced activation of both promoters. Similar elements were also found in other IRF-8 target genes with a consensus sequence (GAAANN[N]GGAA) comprising a core IRF-binding motif and an Ets-binding motif; this sequence is similar but distinct from the previously reported Ets/IRF composite element. Chromatin immunoprecipitation assays demonstrated that IRF-8 and the PU.1 Ets transcription factor bind to this element in vivo. Collectively, these data indicate that IRF-8 stimulates transcription of target genes through a novel cis element to specify macrophage differentiation.
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ICSBP/IRF-8 inhibits mitogenic activity of p210 Bcr/Abl in differentiating Myeloid progenitor Cells
Blood, 2003Co-Authors: Tomohiko Tamura, Hideki Tsujimura, Keiko Ozato, Hee Jeong Kong, Chainarong Tunyaplin, Kathryn CalameAbstract:Interferon consensus sequence binding protein/interferon regulatory factor 8 (ICSBP/IRF-8) is a transcription factor that controls Myeloid Cell Development. ICSBP-/- mice develop a chronic myelogenous leukemia (CML)-like syndrome. Several observations on patients and mouse models have implicated ICSBP in the pathogenesis of CML. In this paper, we investigated whether ICSBP modulates the growth-promoting activity of Bcr/Abl, the causal oncoprotein for CML. When transformed with p210 Bcr/Abl, ICSBP-/- Myeloid progenitor Cells lost growth factor dependence and grew in the absence of granulocyte-macrophage colony-stimulating factor. When ICSBP was ectopically expressed, Bcr/Abl-transformed Cells underwent complete growth arrest and differentiated into mature, functional macrophages without inhibiting the kinase activity of Bcr/Abl. Providing a mechanistic basis for the growth arrest, ICSBP markedly repressed c-Myc messenger RNA (mRNA)-expression, a downstream target of Bcr/Abl. A further analysis with the ICSBP/estrogen receptor chimera showed that ICSBP repression of c-Myc is indirect and is mediated by another gene(s). We identified Blimp-1 and METS/PE1, potent c-Myc repressors, as direct targets of ICSBP activated in these Cells. Consistent with this, ectopic Blimp-1 repressed c-Myc expression and inhibited Cell growth. These results indicate that ICSBP inhibits growth of Bcr/Abl-transformed Myeloid progenitor Cells by activating several genes that interfere with the c-Myc pathway.
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ifn consensus sequence binding protein ifn regulatory factor 8 guides bone marrow progenitor Cells toward the macrophage lineage
Journal of Immunology, 2002Co-Authors: Hideki Tsujimura, Tomohiko Tamura, Tokiko Nagamurainoue, Keiko OzatoAbstract:IFN consensus sequence binding protein (ICSBP; IFN regulatory factor-8) is a transcription factor of the IFN regulatory factor family. Disruption of this gene results in a leukemia-like disease in mice. To investigate the role of ICSBP in Myeloid Cell Development, lineage marker-negative (Lin−) bone marrow progenitor Cells were purified from ICSBP+/+ and ICSBP−/− mice and tested for gene expression and colony-forming ability. ICSBP was expressed in Lin− progenitor Cells, and its levels were markedly increased by IFN-γ. The colony-forming potential of ICSBP−/− progenitor Cells was grossly abnormal, as they gave rise to a disproportionately high number of granulocyte colonies and many fewer macrophage colonies. IFN-γ inhibited colony formation, while promoting macrophage maturation in ICSBP+/+ Cells. In contrast, the effects of IFN-γ were completely absent in ICSBP−/− progenitors. By retrovirus transduction we tested whether reintroduction of ICSBP restores a normal colony-forming potential in −/− progenitor Cells. The wild-type ICSBP, but not transcriptionally defective mutants, corrected abnormal colony formation by increasing macrophage colonies and decreasing granulocyte colonies. Taken together, ICSBP plays a critical role in Myeloid Cell Development by controlling lineage selection and is indispensable for IFN-γ-dependent modulation of progenitor Cell maturation.
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IFN Consensus Sequence Binding Protein/IFN Regulatory Factor-8 Guides Bone Marrow Progenitor Cells Toward the Macrophage Lineage
The Journal of Immunology, 2002Co-Authors: Hideki Tsujimura, Tomohiko Tamura, Tokiko Nagamura-inoue, Keiko OzatoAbstract:IFN consensus sequence binding protein (ICSBP; IFN regulatory factor-8) is a transcription factor of the IFN regulatory factor family. Disruption of this gene results in a leukemia-like disease in mice. To investigate the role of ICSBP in Myeloid Cell Development, lineage marker-negative (Lin−) bone marrow progenitor Cells were purified from ICSBP+/+ and ICSBP−/− mice and tested for gene expression and colony-forming ability. ICSBP was expressed in Lin− progenitor Cells, and its levels were markedly increased by IFN-γ. The colony-forming potential of ICSBP−/− progenitor Cells was grossly abnormal, as they gave rise to a disproportionately high number of granulocyte colonies and many fewer macrophage colonies. IFN-γ inhibited colony formation, while promoting macrophage maturation in ICSBP+/+ Cells. In contrast, the effects of IFN-γ were completely absent in ICSBP−/− progenitors. By retrovirus transduction we tested whether reintroduction of ICSBP restores a normal colony-forming potential in −/− progenitor Cells. The wild-type ICSBP, but not transcriptionally defective mutants, corrected abnormal colony formation by increasing macrophage colonies and decreasing granulocyte colonies. Taken together, ICSBP plays a critical role in Myeloid Cell Development by controlling lineage selection and is indispensable for IFN-γ-dependent modulation of progenitor Cell maturation.
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ICSBP Directs Bipotential Myeloid Progenitor Cells to Differentiate into Mature Macrophages
Immunity, 2000Co-Authors: Tomohiko Tamura, Tokiko Nagamura-inoue, Zeevik Shmeltzer, Takeshi Kuwata, Keiko OzatoAbstract:Abstract During hematopoiesis, Myeloid progenitor Cells give rise to granulocytes and macrophages. To study the role for ICSBP, a hematopoietic Cell-specific transcription factor in Myeloid Cell Development, the gene was introduced into Myeloid progenitor Cells established from ICSBP −/− mice. ICSBP retrovirus-transduced Cells differentiated into mature macrophages with phagocytic activity, which coincided with the induction of specific target DNA binding activity. Similar to macrophages in vivo, ICSBP-transduced Cells were growth arrested, expressed many macrophage-specific genes, and responded to macrophage activation signals. Contrary to this, ICSBP transducion led to repression of granulocyte-specific genes and inhibited G-CSF-mediated granulocytic differentiation in these and other Myeloid progenitor Cells. Together, ICSBP has a key role in the Myeloid Cell lineage selection and macrophage maturation.
Alan G Rosmarin - One of the best experts on this subject based on the ideXlab platform.
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GABP Transcription Factor Is Required for Myeloid Cell Development In Vivo .
Blood, 2007Co-Authors: Zhong-fa Yang, Karen Drumea, Alan G RosmarinAbstract:GABP is an ets transcription factor that regulates genes that are required for innate immunity, including CD18 (β2 leukocyte integrin), lysozyme, and neutrophil elastase. GABP consists of two distinct and unrelated proteins. GABPα binds to DNA through its ets domain and recruits GABPβ, which contains the transactivation domain; together, they form a functional tetrameric transcription factor complex. We recently showed that GABP is required for entry into S phase of the Cell cycle through its regulation of genes that are required for DNA synthesis and cyclin dependent kinase inhibitors (Yang, et al. Nature Cell Biol9:339, 2007). Furthermore, GABP is an essential component of a retinoic acid responsive Myeloid enhanceosome (Resendes and Rosmarin Mol Cell Biol26:3060, 2006). We cloned Gabpa (the gene that encodes mouse Gabpα) from a mouse genomic BAC library and prepared a targeting vector in which the ets domain is flanked by loxP recombination sites (floxed allele). Deletion of both floxed Gabpa alleles causes an early embryonic lethal defect. In order to define the role of Gabpα in myelopoiesis, we bred floxed Gabpa mice to mice that bear the Mx1-Cre transgene, which drives expression of Cre recombinase in response to injection of the synthetic polynucleotide, poly I-C. Deletion of Gabpa dramatically reduced granulocytes and monocytes in the peripheral blood, spleen, and bone marrow, but Myeloid Cells recovered within weeks. In vitro colony forming assays indicated that Myeloid Cells in these mice were derived only from Gabpa replete Myeloid precursors (that failed to delete both Gabpa alleles), suggesting strong pressure to retain Gabpα in vivo . We used a novel competitive bone marrow transplantation approach to determine if Gabp is required for Myeloid Cell Development in vivo . Sub-lethally irradiated wild-type recipient mice bearing leukocyte marker CD45.1 received equal proportions of bone marrow from wild type CD45.1 donor mice and floxed-Mx1-Cre donor mice that bear CD45.2. Both the CD45.2 (floxed-Mx1-Cre) and CD45.1 (wild type) bone marrow engrafted well. Mice were then injected with pI-pC to induce Cre-mediated deletion of floxed Gabpa . The mature Myeloid and T Cell compartments were derived almost entirely from wild type CD45.1 Cells. This indicates that the proliferation and/or differentiation of Myeloid and T Cell lineages requires Gabp. In contrast, B Cell Development was not impaired. We conclude that Gabpa disruption causes a striking loss of Myeloid Cells i n vivo and corroborates prior in vitro data that GABP plays a crucial role in proliferation of Myeloid progenitor Cells.
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GA Binding Protein (GABP) Is Required for Myeloid Cell Development and Differentiation.
Blood, 2005Co-Authors: Karen Drumea, Zhong-fa Yang, Alan G RosmarinAbstract:GABPα is an ets transcription factor that regulates genes that are required for innate immunity, including CD18 (β2 leukocyte integrin), lysozyme, and neutrophil elastase. GABP consists of two distinct and unrelated proteins that, together, form a functional transcription factor complex. GABPα binds to DNA through its ets domain and forms a multimeric complex by recruiting its partner, GABPβ, which contains the transactivation domain. GABPα is a single copy gene in both the human and murine genomes and it is the only protein that can recruit GABPβ to DNA. We cloned GABPα from a murine genomic BAC library and prepared a targeting vector in which the GABPα ets domain is flanked by loxP recombination sites (floxed allele, designated fl). Mice that bear one intact (and one disrupted copy) of GABPα, i.e. hemizygous mice, are phenotypically normal. Intercrossing of hemizygous mice yielded no nullizygous mice, indicating that homozygous loss of GABPα causes an embryonic lethal defect. To determine the effect of GABPα deletion on Myeloid Cell Development, we bred heterozygous and homozygous floxed mice to mice that bear the interferon-responsive Mx1-Cre transgene, which express Cre in response to injection of the synthetic polynucleotide, poly I-C. Bone marrow Cells underwent efficient deletion of GABPα following poly I-C injection; in contrast, other somatic tissues did not efficiently delete the floxed allele. Bone marrow, peripheral blood, and other tissues were examined for Cellular morphology and flow cytometry. We compared mice that lack GABPα in bone marrow ( i.e . fl/fl Mx1-Cre mice injected with poly I-C) to littermate controls ( i.e . fl/fl mice injected with poly I-C). Mice that lack GABPα exhibited a striking and statistically significant decrease in granulocytes and monocytes in bone marrow and peripheral blood, compared with controls; in contrast, there was an increase in erythroid Cells in GABPα null bone marrow. This indicates that the loss of GABPα has lineage-specific effects on Myeloid Cell Development. Morphologic analysis indicates that mice which lack GABPα possess more immature granulocytes compared to control mice. Thus, GABP disruption causes a striking loss of Myeloid Cells in the bone marrow and peripheral blood of mice in a lineage-specific manner. Furthermore, the maturation block of murine granulocytes that is caused by GABPα disruption demonstrates the crucial role of GABP in Myeloid differentiation.
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transcriptional regulation in myelopoiesis hematopoietic fate choice Myeloid differentiation and leukemogenesis
Experimental Hematology, 2005Co-Authors: Alan G Rosmarin, Zhong-fa Yang, Karen K ResendesAbstract:Myeloid Cells (granulocytes and monocytes) are derived from multipotent hematopoietic stem Cells. Gene transcription plays a critical role in hematopoietic differentiation. However, there is no single transcription factor that is expressed exclusively by Myeloid Cells and that, alone, acts as a "master" regulator of Myeloid fate choice. Rather, Myeloid gene expression is controlled by the combinatorial effects of several key transcription factors. Hematopoiesis has traditionally been viewed as linear and hierarchical, but there is increasing evidence of plasticity during blood Cell Development. Transcription factors strongly influence Cellular lineage during hematopoiesis and expression of some transcription factors can alter the fate of developing hematopoietic progenitor Cells. PU.1 and CCAAT/enhancer-binding protein α (C/EBPα) regulate expression of numerous Myeloid genes, and gene disruption studies have shown that they play essential, nonredundant roles in Myeloid Cell Development. They function in cooperation with other transcription factors, co-activators, and co-repressors to regulate genes in the context of chromatin. Because of their essential roles in regulating Myeloid genes and in Myeloid Cell Development, it has been hypothesized that abnormal expression of PU.1 and C/EBPα would contribute to aberrant Myeloid differentiation, i.e. acute leukemia. Such a direct link has been elusive until recently. However, there is now persuasive evidence that mutations in both PU.1 and C/EBPα contribute directly to Development of acute myelogenous leukemia. Thus, normal Myeloid Development and acute leukemia are now understood to represent opposite sides of the same hematopoietic coin.
Xinyu Tian - One of the best experts on this subject based on the ideXlab platform.
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Long Non-Coding RNA HOXA Transcript Antisense RNA Myeloid-Specific 1-HOXA1 Axis Downregulates the Immunosuppressive Activity of Myeloid-Derived Suppressor Cells in Lung Cancer.
Frontiers in Immunology, 2018Co-Authors: Xinyu Tian, Shengjun Wang, Ting Wang, Jie Tian, Yue Zhang, Lingxiang MaoAbstract:HOXA transcript antisense RNA Myeloid-specific 1 (HOTAIRM1) is a long non-coding RNA that has been shown to be a key regulator of Myeloid Cell Development by targeting HOXA1. Myeloid-derived suppressor Cells (MDSCs) are a heterogeneous population of immature Myeloid Cells that possess immunosuppressive function. However, the impact of HOTAIRM1 on the Development of MDSCs remains unknown. In this study, we demonstrated that HOTAIRM1 was expressed in MDSCs and that over-expression of HOTAIRM1 could down-regulate the expression of suppressive molecules in MDSCs. In addition, HOTAIRM1 levels were observed to be decreased in the peripheral blood Cells of lung cancer patients compared to those of healthy controls. By analysing HOTAIRM1 expression levels in different types of lung cancer, we found that HOTAIRM1 was mainly expressed in lung adenocarcinoma. Finally, it was confirmed that HOTAIRM1 could enhance the expression of HOXA1 in MDSCs and that high levels of HOXA1, the target gene of HOTAIRM1, could delay tumour progression and enhance the anti-tumour immune response by down-regulating the immunosuppression of MDSCs. Taken together, the present study illustrates that HOTAIRM1/HOXA1 down-regulates the immunosuppressive function of MDSCs and may be a potential therapeutic target in lung cancer.
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long non coding rna hoxa transcript antisense rna Myeloid specific 1 hoxa1 axis downregulates the immunosuppressive activity of Myeloid derived suppressor Cells in lung cancer
Frontiers in Immunology, 2018Co-Authors: Xinyu Tian, Ting Wang, Jie Tian, Yue Zhang, Lingxiang Mao, Shengjun WangAbstract:HOXA transcript antisense RNA Myeloid-specific 1 (HOTAIRM1) is a long non-coding RNA that has been shown to be a key regulator of Myeloid Cell Development by targeting HOXA1. Myeloid-derived suppressor Cells (MDSCs) are a heterogeneous population of immature Myeloid Cells that possess immunosuppressive function. However, the impact of HOTAIRM1 on the Development of MDSCs remains unknown. In this study, we demonstrated that HOTAIRM1 was expressed in MDSCs and that overexpression of HOTAIRM1 could downregulate the expression of suppressive molecules in MDSCs. In addition, HOTAIRM1 levels were observed to be decreased in the peripheral blood Cells of lung cancer patients compared with those of healthy controls. By analyzing HOTAIRM1 expression levels in different types of lung cancer, we found that HOTAIRM1 was mainly expressed in lung adenocarcinoma. Finally, it was confirmed that HOTAIRM1 could enhance the expression of HOXA1 in MDSCs and that high levels of HOXA1, the target gene of HOTAIRM1, could delay tumor progression and enhance the antitumor immune response by downregulating the immunosuppression of MDSCs. Taken together, this study illustrates that HOTAIRM1/HOXA1 downregulates the immunosuppressive function of MDSCs and may be a potential therapeutic target in lung cancer.
