The Experts below are selected from a list of 222 Experts worldwide ranked by ideXlab platform
Wanggang Zhang - One of the best experts on this subject based on the ideXlab platform.
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pbk topk mediates Promyelocyte proliferation via nrf2 regulated cell cycle progression and apoptosis
Oncology Reports, 2015Co-Authors: Yuhong Liu, Hui Liu, Huiqin Cao, Bin Song, Wen Zhang, Wanggang ZhangAbstract:Acute myeloid leukemia (AML) is a disorder involving hematopoietic stem cells, characterized by blockage of hematopoietic cell differentiation and an increase in clonal neoplastic proliferation. AML is associated with poor patient outcome. PBK/TOPK is a protein kinase derived from PDZ-binding kinase (PBK)/T-lymphokine-activated killer (T-LAK) cell-originated protein kinase (TOPK). Previous studies have shown that PBK/TOPK is expressed in hematologic tumors. In the present study, we aimed to investigate the role of PBK/TOPK in Promyelocyte proliferation and to clarify the molecular mechanism. PBK/TOPK knockdown (KD) significantly decreased cell proliferation and viability in the NB4 and HL-60 Promyelocytes. PBK/TOPK KD resulted in G2/M cell cycle arrest that attributed to a decrease in cdc2 and cyclin B expression. In addition, PBK/TOPK KD caused apoptosis, as evidenced by activation of the mitochondrial apoptotic pathway and an increase in TUNEL-positive cells. PBK/TOPK KD induced mitochondrial dysfunction and ROS generation, and inhibition of mitochondrial dysfunction and ROS production suppressed PBK/TOPK KD-induced cell cycle arrest and apoptosis. Moreover, PBK/TOPK KD decreased Nrf2 expression and ARE-binding activity. Overexpression of Nrf2 inhibited the PBK/TOPK KD-induced decrease in cdc2 and cyclin B expression and cell cycle arrest, and blocked ROS production and apoptosis. Based on literature and our results, it was demonstrated that Nrf2 may be a crucial regulator that mediates PBK/TOPK-exerted promotion of cell proliferation. PBK/TOPK stabilizes Nrf2, strictly regulates the ROS level, promotes cell cycle progression and inhibits apoptosis, contributing to the proliferation of Promyelocytes. Our results provide new insights into the molecular mechanism of PBK/TOPK-mediated Promyelocyte proliferation and shed light on the pathogenesis of AML.
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PBK/TOPK mediates Promyelocyte proliferation via Nrf2-regulated cell cycle progression and apoptosis.
Oncology reports, 2015Co-Authors: Yuhong Liu, Hui Liu, Huiqin Cao, Bin Song, Wen Zhang, Wanggang ZhangAbstract:Acute myeloid leukemia (AML) is a disorder involving hematopoietic stem cells, characterized by blockage of hematopoietic cell differentiation and an increase in clonal neoplastic proliferation. AML is associated with poor patient outcome. PBK/TOPK is a protein kinase derived from PDZ-binding kinase (PBK)/T-lymphokine-activated killer (T-LAK) cell-originated protein kinase (TOPK). Previous studies have shown that PBK/TOPK is expressed in hematologic tumors. In the present study, we aimed to investigate the role of PBK/TOPK in Promyelocyte proliferation and to clarify the molecular mechanism. PBK/TOPK knockdown (KD) significantly decreased cell proliferation and viability in the NB4 and HL-60 Promyelocytes. PBK/TOPK KD resulted in G2/M cell cycle arrest that attributed to a decrease in cdc2 and cyclin B expression. In addition, PBK/TOPK KD caused apoptosis, as evidenced by activation of the mitochondrial apoptotic pathway and an increase in TUNEL-positive cells. PBK/TOPK KD induced mitochondrial dysfunction and ROS generation, and inhibition of mitochondrial dysfunction and ROS production suppressed PBK/TOPK KD-induced cell cycle arrest and apoptosis. Moreover, PBK/TOPK KD decreased Nrf2 expression and ARE-binding activity. Overexpression of Nrf2 inhibited the PBK/TOPK KD-induced decrease in cdc2 and cyclin B expression and cell cycle arrest, and blocked ROS production and apoptosis. Based on literature and our results, it was demonstrated that Nrf2 may be a crucial regulator that mediates PBK/TOPK-exerted promotion of cell proliferation. PBK/TOPK stabilizes Nrf2, strictly regulates the ROS level, promotes cell cycle progression and inhibits apoptosis, contributing to the proliferation of Promyelocytes. Our results provide new insights into the molecular mechanism of PBK/TOPK-mediated Promyelocyte proliferation and shed light on the pathogenesis of AML.
Armin Buschauer - One of the best experts on this subject based on the ideXlab platform.
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histamine increases cytosolic ca2 in hl 60 Promyelocytes predominantly via h2 receptors with an unique agonist antagonist profile and induces functional differentiation
Molecular Pharmacology, 1992Co-Authors: Roland Seifert, A Hoer, I Schwaner, Armin BuschauerAbstract:Histamine H1 receptors mediate activation of phospholipase C, with subsequent increases in cytosolic Ca2+ concentration ([Ca2+]i), and H2 receptors mediate accumulation of cAMP. HL-60 Promyelocytes possess H2 receptors, but it is not known whether these cells also possess H1 receptors. We studied the effects of histamine on [Ca2+]i and the functional importance of histamine receptors in HL-60 Promyelocytes. In these cells, histamine and dimaprit increased [Ca2+]i with EC50 values of 15 microM and 30 microM, respectively. Diphenhydramine inhibited the effect of histamine (100 microM) on [Ca2+]i up to 40%, with an IC50 of 100 nM. Famotidine and cimetidine diminished the effect of histamine (100 microM) up to 75%, with IC50 values of 85 nM and 300 nM, respectively. Diphenhydramine plus famotidine abolished histamine-induced rises in [Ca2+]i. Impromidine, with an IC50 of 100 nM, abolished the effect of histamine (100 microM) on [Ca2+]i. Diphenhydramine, famotidine, cimetidine, and impromidine showed marked noncompetitive antagonism with histamine. Histamine-induced increases in [Ca2+]i were largely due to influx of Ca2+ from the extracellular space. Ca2+ influx was inhibited by 1-(beta-[3-(4-methoxyphenyl)propoxyl]-4-methoxyphenethyl)-1H-imida zole hydrochloride (SK&F 96365). Histamine activated phospholipase C. Histamine induced expression of formyl peptide receptors, which effect was abolished by famotidine. In U-937 promonocytes and in the human erythroleukemia cell lines HEL and K-562, histamine did not induce rises in [Ca2+]i. Our data suggest the following. (i) In HL-60 Promyelocytes, histamine increases [Ca2+]i predominantly via H2 receptors and to a lesser extent via H1 receptors. (ii) The agonist/antagonist profile of the H2 receptor-mediated increases in [Ca2+]i differs markedly from that for cAMP accumulation, suggesting the involvement of different H2 receptor subtypes. (iii) In HL-60 Promyelocytes, histamine activates nonselective cation channels and induces functional differentiation via H2 receptors.
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Histamine increases cytosolic Ca2+ in HL-60 Promyelocytes predominantly via H2 receptors with an unique agonist/antagonist profile and induces functional differentiation.
Molecular pharmacology, 1992Co-Authors: Roland Seifert, A Hoer, I Schwaner, Armin BuschauerAbstract:Histamine H1 receptors mediate activation of phospholipase C, with subsequent increases in cytosolic Ca2+ concentration ([Ca2+]i), and H2 receptors mediate accumulation of cAMP. HL-60 Promyelocytes possess H2 receptors, but it is not known whether these cells also possess H1 receptors. We studied the effects of histamine on [Ca2+]i and the functional importance of histamine receptors in HL-60 Promyelocytes. In these cells, histamine and dimaprit increased [Ca2+]i with EC50 values of 15 microM and 30 microM, respectively. Diphenhydramine inhibited the effect of histamine (100 microM) on [Ca2+]i up to 40%, with an IC50 of 100 nM. Famotidine and cimetidine diminished the effect of histamine (100 microM) up to 75%, with IC50 values of 85 nM and 300 nM, respectively. Diphenhydramine plus famotidine abolished histamine-induced rises in [Ca2+]i. Impromidine, with an IC50 of 100 nM, abolished the effect of histamine (100 microM) on [Ca2+]i. Diphenhydramine, famotidine, cimetidine, and impromidine showed marked noncompetitive antagonism with histamine. Histamine-induced increases in [Ca2+]i were largely due to influx of Ca2+ from the extracellular space. Ca2+ influx was inhibited by 1-(beta-[3-(4-methoxyphenyl)propoxyl]-4-methoxyphenethyl)-1H-imida zole hydrochloride (SK&F 96365). Histamine activated phospholipase C. Histamine induced expression of formyl peptide receptors, which effect was abolished by famotidine. In U-937 promonocytes and in the human erythroleukemia cell lines HEL and K-562, histamine did not induce rises in [Ca2+]i. Our data suggest the following. (i) In HL-60 Promyelocytes, histamine increases [Ca2+]i predominantly via H2 receptors and to a lesser extent via H1 receptors. (ii) The agonist/antagonist profile of the H2 receptor-mediated increases in [Ca2+]i differs markedly from that for cAMP accumulation, suggesting the involvement of different H2 receptor subtypes. (iii) In HL-60 Promyelocytes, histamine activates nonselective cation channels and induces functional differentiation via H2 receptors.
Yuhong Liu - One of the best experts on this subject based on the ideXlab platform.
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pbk topk mediates Promyelocyte proliferation via nrf2 regulated cell cycle progression and apoptosis
Oncology Reports, 2015Co-Authors: Yuhong Liu, Hui Liu, Huiqin Cao, Bin Song, Wen Zhang, Wanggang ZhangAbstract:Acute myeloid leukemia (AML) is a disorder involving hematopoietic stem cells, characterized by blockage of hematopoietic cell differentiation and an increase in clonal neoplastic proliferation. AML is associated with poor patient outcome. PBK/TOPK is a protein kinase derived from PDZ-binding kinase (PBK)/T-lymphokine-activated killer (T-LAK) cell-originated protein kinase (TOPK). Previous studies have shown that PBK/TOPK is expressed in hematologic tumors. In the present study, we aimed to investigate the role of PBK/TOPK in Promyelocyte proliferation and to clarify the molecular mechanism. PBK/TOPK knockdown (KD) significantly decreased cell proliferation and viability in the NB4 and HL-60 Promyelocytes. PBK/TOPK KD resulted in G2/M cell cycle arrest that attributed to a decrease in cdc2 and cyclin B expression. In addition, PBK/TOPK KD caused apoptosis, as evidenced by activation of the mitochondrial apoptotic pathway and an increase in TUNEL-positive cells. PBK/TOPK KD induced mitochondrial dysfunction and ROS generation, and inhibition of mitochondrial dysfunction and ROS production suppressed PBK/TOPK KD-induced cell cycle arrest and apoptosis. Moreover, PBK/TOPK KD decreased Nrf2 expression and ARE-binding activity. Overexpression of Nrf2 inhibited the PBK/TOPK KD-induced decrease in cdc2 and cyclin B expression and cell cycle arrest, and blocked ROS production and apoptosis. Based on literature and our results, it was demonstrated that Nrf2 may be a crucial regulator that mediates PBK/TOPK-exerted promotion of cell proliferation. PBK/TOPK stabilizes Nrf2, strictly regulates the ROS level, promotes cell cycle progression and inhibits apoptosis, contributing to the proliferation of Promyelocytes. Our results provide new insights into the molecular mechanism of PBK/TOPK-mediated Promyelocyte proliferation and shed light on the pathogenesis of AML.
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PBK/TOPK mediates Promyelocyte proliferation via Nrf2-regulated cell cycle progression and apoptosis.
Oncology reports, 2015Co-Authors: Yuhong Liu, Hui Liu, Huiqin Cao, Bin Song, Wen Zhang, Wanggang ZhangAbstract:Acute myeloid leukemia (AML) is a disorder involving hematopoietic stem cells, characterized by blockage of hematopoietic cell differentiation and an increase in clonal neoplastic proliferation. AML is associated with poor patient outcome. PBK/TOPK is a protein kinase derived from PDZ-binding kinase (PBK)/T-lymphokine-activated killer (T-LAK) cell-originated protein kinase (TOPK). Previous studies have shown that PBK/TOPK is expressed in hematologic tumors. In the present study, we aimed to investigate the role of PBK/TOPK in Promyelocyte proliferation and to clarify the molecular mechanism. PBK/TOPK knockdown (KD) significantly decreased cell proliferation and viability in the NB4 and HL-60 Promyelocytes. PBK/TOPK KD resulted in G2/M cell cycle arrest that attributed to a decrease in cdc2 and cyclin B expression. In addition, PBK/TOPK KD caused apoptosis, as evidenced by activation of the mitochondrial apoptotic pathway and an increase in TUNEL-positive cells. PBK/TOPK KD induced mitochondrial dysfunction and ROS generation, and inhibition of mitochondrial dysfunction and ROS production suppressed PBK/TOPK KD-induced cell cycle arrest and apoptosis. Moreover, PBK/TOPK KD decreased Nrf2 expression and ARE-binding activity. Overexpression of Nrf2 inhibited the PBK/TOPK KD-induced decrease in cdc2 and cyclin B expression and cell cycle arrest, and blocked ROS production and apoptosis. Based on literature and our results, it was demonstrated that Nrf2 may be a crucial regulator that mediates PBK/TOPK-exerted promotion of cell proliferation. PBK/TOPK stabilizes Nrf2, strictly regulates the ROS level, promotes cell cycle progression and inhibits apoptosis, contributing to the proliferation of Promyelocytes. Our results provide new insights into the molecular mechanism of PBK/TOPK-mediated Promyelocyte proliferation and shed light on the pathogenesis of AML.
Scott C. Kogan - One of the best experts on this subject based on the ideXlab platform.
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identification of irf8 as a potent tumor suppressor in murine acute promyelocytic leukemia
Blood Advances, 2018Co-Authors: Coline Gaillard, Sangeetha Surianarayanan, Trevor Bentley, Matthew R Warr, Briana Fitch, Huimin Geng, Emmanuelle Passegue, Scott C. KoganAbstract:Although the role of promyelocytic leukemia/retinoic acid receptor α (PML/RARA) fusion protein is well recognized in acute promyelocytic leukemia (APL), its contribution to initiation and maintenance of leukemogenesis is not completely understood. Transcriptome analysis in the murine MRP8-PML/RARA APL model has demonstrated modest alterations in gene expression accompanied by expansion of the Promyelocyte compartment. Of particular interest, mice expressing PML/RARA showed downregulation of the transcription factor Irf8 mRNA. Interferon regulatory factor 8 (IRF8) is a known regulator of hematopoiesis. Previous research had implicated IRF8 as a tumor suppressor for myeloid neoplasia, and mice lacking IRF8 develop a well-differentiated myeloproliferative neoplasm characterized by expansion of neutrophilic lineage cells. We hypothesized that PML/RARA-mediated downregulation of Irf8 transcript levels contributes to the initiation of APL. We observed significant downregulation of IRF8 protein levels in highly purified Promyelocyte populations of PML/RARA transgenic mice. We also found that loss of IRF8 results in expansion of Promyelocytes in vivo, partially phenocopying the impact of PML/RARA expression. Moreover, survival experiments showed that complete loss of IRF8 leads to acceleration of APL onset in our PML/RARA mice. Collectively, these data identify IRF8 downregulation as an important factor in APL initiation and highlight a tumor-suppressor role for IRF8 in this acute leukemia.
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Identification of IRF8 As a Potent Tumor Suppressor in Murine Acute Promyelocytic Leukemia
Blood, 2016Co-Authors: Sangeetha Surianarayanan, Trevor Bentley, Matthew R Warr, Briana Fitch, Huimin Geng, Emmanuelle Passegue, Coline M Gaillard, Scott C. KoganAbstract:Abstract The classical paradigm suggests that PML/RARA fusion protein is the main driver of pathogenesis in APL. It is believed that the fusion oncogenic protein mediates this effect by potentially repressing key myeloid maturation genes involved in differentiation processes. However, the underlying mechanism is not completely understood. We recently challenged this model re-opening fundamental questions as to understand the precise contribution of the fusion protein to leukemic transformation. This knowledge on the mechanistic pathways can lead to better tailored combinatorial therapeutics. To understand the role of the PML/RARA fusion protein in leukemogenesis, we initially did a transcriptome analysis in our murine MRP8-PML/RARA APL model. Interestingly, we observed only moderate alterations in gene expression pattern of the key myeloid genes that we thought to be actively involved in differentiation processes. Of particular note, we found significant downregulation of the Irf8 in our Promyelocyte compartments. IRF8 is a known regulator of hematopoiesis. The IRF8 myeloid transcription factor (TF) is expressed in several lineages of the hematopoietic tree and plays an important role in orchestrating specification and differentiation of B cells, dendritic cells and monocytes. Herein, we speculate lower levels of IRF8 could potentially impact tumorigenesis in the context of PML/RARA. In order to address this question, technically, we employed stringent staining and sorting strategy to distinctly differentiate early and late Promyelocytes and looked at the expression pattern of Irf8 gene both at the transcript and protein levels. Results from qRT-PCR demonstrated 4.8 fold decrease in Irf8 expression compared to wildtype controls both in preleukemic Promyelocytes and fully differentiated leukemic cells suggesting PML/RARA could be a target of IRF8 and this association could potentially be involved in the emergence and maintenance of leukemia. We next asked whether these changes are reflective at the protein levels and performed a Western blot analysis in our highly purified Promyelocyte population and found a dramatic decrease in IRF8 levels in comparison to wild type controls again suggesting a possible protein-protein interaction under normal conditions that may provide an advantage for the cells from turning oncogenic. In order to study how low levels of IRF8 impact Promyelocyte expansion, we generated double knock-outs of mice harboring both PML/RARA Irf8-/- mutations and compared their phenotype with mice harboring single mutations in either PML/RARA or Irf8 gene. As previously observed, young PML/RARA mice had a substantially increased number of marrow Promyelocytes in comparison to wild-type mice. Fascinatingly, loss of Irf8 alone resulted in an essentially identical expansion of Promyelocytes (as well as a loss of earlier myeloid progenitors in the bone marrow, not seen in PML/RARA mice) and a combination of PML/RARA expression and IRF8 loss did not result in a statistically significant further expansion of Promyelocytes. These results suggest an epistatic relationship between PML/RARA and IRF8, compatible with downregulation of IRF8 by PML/RARA as being a key mechanism by which t(15;17) expands Promyelocytes in the initiation of APL. Furthermore, in order to assess the impact of single/double genetic alterations on the overall and leukemia free survival we transplanted lethally irradiated mice with bone marrow cells derived from PML/RARA, Irf8-/- and PML/RARA Irf8-/-double knock outs and followed these mice over a period of one year. We observed there is no difference in their overall survival rate among the different groups of mice. However, looking specifically at the acute leukemic deaths, we observed a reduced latency in our PML/RARA Irf8-/- cohorts compared to mice carrying single mutation at PML/RARA loci. We also noticed that all the acute leukemias in the PML/RARA Irf8-/- cohort occurred prior to the first appearance of acute leukemia in the PML/RARA cohorts. Altogether, these data support a model of APL leukemogenesis in which the translocation of chromosomes 15 and 17 initiates leukemia development, in part by downregulating IRF8, and in which the resulting expansion of the Promyelocyte compartment contributes to acquisition of additional cooperating events (e.g. trisomy of chromosome 8, mutation of FLT3) that complete leukemic transformation. Disclosures No relevant conflicts of interest to declare.
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Transcription and methylation analyses of preleukemic Promyelocytes indicate a dual role for PML/RARA in leukemia initiation
Haematologica, 2015Co-Authors: Coline Gaillard, Emmanuelle Passegue, Taku Tokuyasu, Galit Rosen, Jason Sotzen, Adeline Vitaliano-prunier, Ritu Roy, Maria E. Figueroa, Scott C. KoganAbstract: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.
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PML-RARα Deregulates an Unexpectedly Small Number of Genes in Pre-Leukemic Promyelocytes
Blood, 2012Co-Authors: Coline Gaillard, Emmanuelle Passegue, Taku Tokuyasu, Scott C. KoganAbstract:Abstract 3526 Background: Acute Promyelocytic Leukemia (APL) is characterized by the accumulation in the blood and bone marrow of abnormal Promyelocytes, which have the ability to transfer the disease to secondary recipients in animal models. The PML-RARα fusion protein is thought to be the primary abnormality implicated in the pathology, and is believed to prevent transcription of genes necessary for normal myeloid development and differentiation. Identifying PML-RARα targets is critical for understanding the road to leukemic transformation. However, such targets have so far been identified using cell line assays in vitro , murine cells differentiated into Promyelocytes in vitro , or fully transformed murine or human leukemic cells. Focusing on the cell population in which the transforming potential is acquired, we describe here a novel strategy to identify the transcriptomic dysregulation induced by PML-RARα expression in maturing myeloid populations in vivo . Methods: We utilize a murine model of human APL in which the human PML-RARα fusion gene is expressed under the control of the MRP8 promoter, driving its expression in maturing myeloid populations. Those animals can be described as pre-leukemic since they eventually develop leukemia when additional mutations occur. Fresh bone marrows from normal (Fvb/n) or pre-leukemic (PML-RARα) animals were harvested. Using an improved cell surface antigen staining strategy and fluorescence-activated cell sorting, three populations of increasingly differentiated myeloid populations have been sorted (Granulocyte Macrophage Progenitor, Early Promyelocyte and Late Promyelocyte). RNA was extracted and submitted for whole-genome microarray analysis. In addition, we are using a variety of bioinformatics approaches to decipher the network of novel interactions driven by PML-RARα expression. Results: Markers used in our sorting strategy were validated in the dataset, including CD34 and Gr1 . In the normal samples, markers of neutrophil maturation increased, largely as expected, and a number of early transcription factors decreased in an expected manner including Hoxa9 and Meis1 . One remarkable finding was that despite the previously described ability of PML-RARα to regulate transcription from multiple sites in the genome, only a small number of genes were differentially impacted by the expression of this protein. Surprisingly, well-known regulators of myeloid differentiation that have been implicated in the retinoic acid responsiveness of APL including Sfpi1 (PU.1) and Cebpa were not differentially expressed. However, in pre-leukemic samples PML-RARα did cause decreased expression of multiple neutrophilic granule genes including Ltf , Mmp9 and Ngp . The gene most upregulated in the pre-leukemic samples was Spp1 which encodes the osteopontin phosphoprotein. Of interest, we identified the myeloid tumor suppressor Irf8 to be downregulated 5 fold in the presence of PML-RARα. To investigate the importance of IRF8 levels in APL initiation, we transplanted Irf8 +/+ PML-RARα or Irf8 +/− PML-RARα bone marrow into irradiated recipients. Despite the potential for decreased expression of IRF8 to contribute to APL, we observed no difference. This result does not confirm a role for IRF8 in APL pathogenesis, but further investigations are needed to exclude such a role. Bioinformatics studies highlighted enrichment in cell cycle-related genes upon PML-RARα expression, suggesting a possible difference in the proliferation capacity of the pre-leukemic cells, which is currently under investigation. Conclusions: We found that in vivo the transcriptome was only modestly dysregulated by the presence of PML-RARα. These observations open up new questions on the role of the fusion protein in pathogenesis: How does PML-RARα prime pre-leukemic cells for full transformation? How do secondary events allow an initiated cell to advance to a fully transformed state? Such questions are currently being investigated, with a special interest on looking at the cooperation between PML-RARα and activated cytokine signaling in leukemia initiation. Disclosures: No relevant conflicts of interest to declare.
Roland Seifert - One of the best experts on this subject based on the ideXlab platform.
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histamine increases cytosolic ca2 in hl 60 Promyelocytes predominantly via h2 receptors with an unique agonist antagonist profile and induces functional differentiation
Molecular Pharmacology, 1992Co-Authors: Roland Seifert, A Hoer, I Schwaner, Armin BuschauerAbstract:Histamine H1 receptors mediate activation of phospholipase C, with subsequent increases in cytosolic Ca2+ concentration ([Ca2+]i), and H2 receptors mediate accumulation of cAMP. HL-60 Promyelocytes possess H2 receptors, but it is not known whether these cells also possess H1 receptors. We studied the effects of histamine on [Ca2+]i and the functional importance of histamine receptors in HL-60 Promyelocytes. In these cells, histamine and dimaprit increased [Ca2+]i with EC50 values of 15 microM and 30 microM, respectively. Diphenhydramine inhibited the effect of histamine (100 microM) on [Ca2+]i up to 40%, with an IC50 of 100 nM. Famotidine and cimetidine diminished the effect of histamine (100 microM) up to 75%, with IC50 values of 85 nM and 300 nM, respectively. Diphenhydramine plus famotidine abolished histamine-induced rises in [Ca2+]i. Impromidine, with an IC50 of 100 nM, abolished the effect of histamine (100 microM) on [Ca2+]i. Diphenhydramine, famotidine, cimetidine, and impromidine showed marked noncompetitive antagonism with histamine. Histamine-induced increases in [Ca2+]i were largely due to influx of Ca2+ from the extracellular space. Ca2+ influx was inhibited by 1-(beta-[3-(4-methoxyphenyl)propoxyl]-4-methoxyphenethyl)-1H-imida zole hydrochloride (SK&F 96365). Histamine activated phospholipase C. Histamine induced expression of formyl peptide receptors, which effect was abolished by famotidine. In U-937 promonocytes and in the human erythroleukemia cell lines HEL and K-562, histamine did not induce rises in [Ca2+]i. Our data suggest the following. (i) In HL-60 Promyelocytes, histamine increases [Ca2+]i predominantly via H2 receptors and to a lesser extent via H1 receptors. (ii) The agonist/antagonist profile of the H2 receptor-mediated increases in [Ca2+]i differs markedly from that for cAMP accumulation, suggesting the involvement of different H2 receptor subtypes. (iii) In HL-60 Promyelocytes, histamine activates nonselective cation channels and induces functional differentiation via H2 receptors.
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Histamine increases cytosolic Ca2+ in HL-60 Promyelocytes predominantly via H2 receptors with an unique agonist/antagonist profile and induces functional differentiation.
Molecular pharmacology, 1992Co-Authors: Roland Seifert, A Hoer, I Schwaner, Armin BuschauerAbstract:Histamine H1 receptors mediate activation of phospholipase C, with subsequent increases in cytosolic Ca2+ concentration ([Ca2+]i), and H2 receptors mediate accumulation of cAMP. HL-60 Promyelocytes possess H2 receptors, but it is not known whether these cells also possess H1 receptors. We studied the effects of histamine on [Ca2+]i and the functional importance of histamine receptors in HL-60 Promyelocytes. In these cells, histamine and dimaprit increased [Ca2+]i with EC50 values of 15 microM and 30 microM, respectively. Diphenhydramine inhibited the effect of histamine (100 microM) on [Ca2+]i up to 40%, with an IC50 of 100 nM. Famotidine and cimetidine diminished the effect of histamine (100 microM) up to 75%, with IC50 values of 85 nM and 300 nM, respectively. Diphenhydramine plus famotidine abolished histamine-induced rises in [Ca2+]i. Impromidine, with an IC50 of 100 nM, abolished the effect of histamine (100 microM) on [Ca2+]i. Diphenhydramine, famotidine, cimetidine, and impromidine showed marked noncompetitive antagonism with histamine. Histamine-induced increases in [Ca2+]i were largely due to influx of Ca2+ from the extracellular space. Ca2+ influx was inhibited by 1-(beta-[3-(4-methoxyphenyl)propoxyl]-4-methoxyphenethyl)-1H-imida zole hydrochloride (SK&F 96365). Histamine activated phospholipase C. Histamine induced expression of formyl peptide receptors, which effect was abolished by famotidine. In U-937 promonocytes and in the human erythroleukemia cell lines HEL and K-562, histamine did not induce rises in [Ca2+]i. Our data suggest the following. (i) In HL-60 Promyelocytes, histamine increases [Ca2+]i predominantly via H2 receptors and to a lesser extent via H1 receptors. (ii) The agonist/antagonist profile of the H2 receptor-mediated increases in [Ca2+]i differs markedly from that for cAMP accumulation, suggesting the involvement of different H2 receptor subtypes. (iii) In HL-60 Promyelocytes, histamine activates nonselective cation channels and induces functional differentiation via H2 receptors.
