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Megakaryocyte

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https://www.readbyqxmd.com/read/28630120/selinexor-induced-thrombocytopenia-results-from-inhibition-of-thrombopoietin-signaling-in-early-megakaryopoiesis
#1
Kellie R Machlus, Stephen K Wu, Prakrith Vijey, Thomas S Soussou, Zhi-Jian Liu, Eran Shacham, T J Unger, Trinayan Kashyap, Boris Klebanov, Martha Sola-Visner, Marsha Crochiere, Joseph E Italiano, Yosef Landesman
Selinexor is the first oral Selective Inhibitor of Nuclear Export compound tested for cancer treatment. Selinexor has demonstrated a safety therapy profile with broad antitumor activity against solid and hematological malignancies in phases 2 and 3 clinical trials (NCT03071276, NCT02343042, NCT02227251, NCT03110562, NCT02606461). While selinexor shows promising efficacy, its primary adverse effect is high-grade thrombocytopenia. Therefore, we aimed to identify the mechanism of selinexor-induced thrombocytopenia to relieve it and improve its clinical management...
June 19, 2017: Blood
https://www.readbyqxmd.com/read/28626802/cohesin-mutations-in-myeloid-malignancies
#2
Joseph B Fisher, Maureen McNulty, Michael J Burke, John D Crispino, Sridhar Rao
Acute Myeloid Leukemia (AML) is a hematologic malignancy with a poor prognosis. Recent genome-wide sequencing studies have identified frequent mutations in genes encoding members of the cohesin complex. Mutations in cohesin contribute to myeloid malignancies by conferring enhanced self-renewal of hematopoietic stem and progenitor cells but the mechanisms behind this phenotype have not been fully elucidated. Of note, cohesin mutations are highly prevalent in acute megakaryocytic leukemia associated with Down syndrome (DS-AMKL), where they occur in over half of patients...
April 2017: Trends in Cancer
https://www.readbyqxmd.com/read/28626367/towards-the-manufacture-of-megakaryocytes-and-platelets-for-clinical-application
#3
REVIEW
Anja Baigger, Rainer Blasczyk, Constanca Figueiredo
Platelet transfusions are used in standard clinical practice to prevent hemorrhage in patients suffering from thrombocytopenia or platelet dysfunctions. Recently, a constant rise on the demand of platelets for transfusion has been registered. This may be associated with several factors including demographic changes, population aging as well as incidence and prevalence of hematological diseases. In addition, platelet-regenerative properties have been started to be exploited in different areas such as tissue remodeling and anti-cancer therapies...
June 2017: Transfusion Medicine and Hemotherapy
https://www.readbyqxmd.com/read/28622305/the-thrombopoietin-mpl-axis-is-activated-in-the-gata1-low-mouse-model-of-myelofibrosis-and-is-associated-with-a-defective-rps14-signature
#4
M Zingariello, L Sancillo, F Martelli, F Ciaffoni, M Marra, L Varricchio, R A Rana, C Zhao, J D Crispino, A R Migliaccio
Myelofibrosis (MF) is characterized by hyperactivation of thrombopoietin (TPO) signaling, which induces a RPS14 deficiency that de-regulates GATA1 in megakaryocytes by hampering its mRNA translation. As mice carrying the hypomorphic Gata1(low) mutation, which reduces the levels of Gata1 mRNA in megakaryocytes, develop MF, we investigated whether the TPO axis is hyperactive in this model. Gata1(low) mice contained two times more Tpo mRNA in liver and TPO in plasma than wild-type littermates. Furthermore, Gata1(low) LSKs expressed levels of Mpl mRNA (five times greater than normal) and protein (two times lower than normal) similar to those expressed by LSKs from TPO-treated wild-type mice...
June 16, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28622093/suppressive-effect-of-dengue-virus-envelope-protein-domain-iii-on-megakaryopoiesis
#5
Guan-Ling Lin, Hsin-Hou Chang, Te-Sheng Lien, Po-Kong Chen, Hao Chan, Mei-Tzu Su, Chi-Yuan Liao, Der-Shan Sun
Dengue virus (DENV) infection can cause severe, life-threatening events, and no specific treatments for DENV infection are currently approved. Although thrombocytopenia is frequently observed in dengue patients, its pathogenesis is still not fully understood. Previous studies have suggested that DENV-induced thrombocytopenia occurs through viral-replication-mediated megakaryopoiesis inhibition in the bone marrow; however, the exact mechanism for megakaryopoiesis suppression remains elusive. In this study, a reductionist approach was applied, in which C57B/6J mice were inoculated with recombinant DENV-envelope protein domain III (DENV-EIII) instead of the full viral particle...
June 16, 2017: Virulence
https://www.readbyqxmd.com/read/28618874/von-willebrand-factor-multimeric-structure-and-functional-activity-in-patients-with-atrial-fibrillation-with-and-without-oral-anticoagulation
#6
Sandra Lopez-Castaneda, Ignacio Valencia-Hernández, Carlos Arean, Daniel Godínez-Hernández, Martha Eva Viveros-Sandoval
von Willebrand factor (vWF) is a multimeric glycoprotein present in blood plasma. It is synthesized in megakaryocytes and endothelial cells, secreted into circulation in the form of high-molecular-weight multimers (HMWMs), and cleaved into shorter, less active multimers by ADAMTS13. It is essential for platelet adhesion and aggregation. Previous studies have investigated the relationship between vWF levels and thromboembolic events with little regard to vWF multimeric structure. Patients with atrial fibrillation (AF) exhibit higher plasma vWF and lower ADAMTS13 levels...
January 1, 2017: Clinical and Applied Thrombosis/hemostasis
https://www.readbyqxmd.com/read/28615442/the-heterotrimeric-g-protein-g%C3%AE-1-interacts-with-the-catalytic-subunit-of-protein-phosphatase-1-and-modulates-g-protein-coupled-receptor-signaling-in-platelets
#7
Subhashree Pradhan, Tanvir Khatlani, Angus C Nairn, K Vinod Vijayan
Thrombosis is caused by the activation of platelets at the site of ruptured atherosclerotic plaques. This activation involves engagement of G protein coupled receptors (GPCR) on platelets that promotes their aggregation. Although it is known that protein kinases and phosphatases modulate GPCR signaling, how serine/threonine phosphatases integrate with G protein signaling pathways is less understood. Since the subcellular localization and substrate specificity of the catalytic subunit of protein phosphatase 1 (PP1c) is dictated by PP1c-interacting proteins, here we sought to identify new PP1c interactors...
June 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28615267/the-novel-association-of-circulating-tumor-cells-and-circulating-megakaryocytes-with-prostate-cancer-prognosis
#8
Lei Xu, Xueying Mao, Tianyu Guo, Pui Ying Chan, Greg Shaw, John Hines, Elzbieta Stankiewicz, Yuqin Wang, R Tim D Oliver, Amar Sabri Ahmad, Daniel Berney, Jonathan Shamash, Yong-Jie Lu
To develop an approach for the investigation of different subtypes of circulating tumor cells (CTCs) and other cells to evaluate their potential prognostic value of prostate cancer.<br /><br />Experimental Design: Malignancy of CTCs undergoing epithelial to mesenchymal transition (EMT) was confirmed by repeated Fluorescence in situ hybridization. Subgroups of CTCs in 81 patients with prostate cancer (43 castration resistant and 38 untreated localized) were correlated to disease aggressiveness parameters...
June 14, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28600522/direct-competition-between-dna-binding-factors-highlights-the-role-of-kr%C3%A3-ppel-like-factor-1-in-the-erythroid-megakaryocyte-switch
#9
Laura J Norton, Samantha Hallal, Elizabeth S Stout, Alister P W Funnell, Richard C M Pearson, Merlin Crossley, Kate G R Quinlan
The Krüppel-like factor (KLF) family of transcription factors play critical roles in haematopoiesis. KLF1, the founding member of the family, has been implicated in the control of both erythropoiesis and megakaryopoiesis. Here we describe a novel system using an artificial dominant negative isoform of KLF1 to investigate the role of KLF1 in the erythroid/megakaryocytic switch in vivo. We developed murine cell lines stably overexpressing a GST-KLF1 DNA binding domain fusion protein (GST-KLF1 DBD), as well as lines expressing GST only as a control...
June 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28596654/is-there-a-relationship-between-cxcr4-gene-expression-and-prognosis-of-immune-thrombocytopenia-in-children
#10
Sajedeh Saeidi, Javad Mohammadi-Asl, Mohammad Ali Jalali Far, Ali Amin Asnafi, Firouzeh Dehuri, Yousef Tavakolifar, Najmaldin Saki
Immune thrombocytopenia (ITP) is a common autoimmune disorder characterized by decreased platelet count (thrombocytopenia) and bleeding symptoms due to production of autoantibodies against platelets. Chemokines are molecules inducing chemotaxis and play an important role in megakaryopoiesis, including CXCR4 chemokine receptor. CXCR4 is expressed on cells of megakaryocytic series, especially platelets, and triggers several mechanisms in these cells. The purpose of this study was to evaluate the pattern of CXCR4 gene changes upon diagnosis and after treatment and its comparison with laboratory findings in peripheral blood samples from newly diagnosed ITP patients...
June 2017: Indian Journal of Hematology & Blood Transfusion
https://www.readbyqxmd.com/read/28596376/cre-lox-studies-identify-resident-macrophages-as-the-major-source-of-circulating-coagulation-factor-xiii-a
#11
Cora M L Beckers, Kingsley R Simpson, Kathryn J Griffin, Jane M Brown, Lih T Cheah, Kerrie A Smith, Jean Vacher, Paul A Cordell, Mark T Kearney, Peter J Grant, Richard J Pease
OBJECTIVE: To establish the cellular source of plasma factor (F)XIII-A. APPROACH AND RESULTS: A novel mouse floxed for the F13a1 gene, FXIII-A(flox/flox) (Flox), was crossed with myeloid- and platelet-cre-expressing mice, and cellular FXIII-A mRNA expression and plasma and platelet FXIII-A levels were measured. The platelet factor 4-cre.Flox cross abolished platelet FXIII-A and reduced plasma FXIII-A to 23±3% (P<0.001). However, the effect of platelet factor 4-cre on plasma FXIII-A was exerted outside of the megakaryocyte lineage because plasma FXIII-A was not reduced in the Mpl(-/-) mouse, despite marked thrombocytopenia...
June 8, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28592432/up-regulation-of-lysyl-oxidase-and-adhesion-to-collagen-of-human-megakaryocytes-and-platelets-in-primary-myelofibrosis
#12
Vittorio Abbonante, Vipul Chitalia, Vittorio Rosti, Orly Leiva, Shinobu Matsuura, Alessandra Balduini, Katya Ravid
No abstract text is available yet for this article.
June 7, 2017: Blood
https://www.readbyqxmd.com/read/28589317/bcl6-gene-silencing-facilitates-pma-induced-megakaryocyte-differentiation-in-k562-cells
#13
Sedigheh Eskandari, Razieh Yazdanparast
Targeted therapy via imatinib appears to be a promising approach for chronic myeloid leukemia (CML) therapy. However, refractory and resistance to imatinib therapy has encouraged many investigators to get involved in development of new therapeutic agents such as Phorbol 12-myrestrat 13-acetate (PMA) for patients with CML. In that line, we attempted to investigate the chemosensitizing effect of PMA on the imatinib-resistant cells. Based on our western blot analyses, resistant K562 cells (K562R) showed high levels of FoxO3a and Bcl6 expressions which were not modulated by imatinib treatment...
June 6, 2017: Journal of Cell Communication and Signaling
https://www.readbyqxmd.com/read/28589084/calreticulin-in-essential-thrombocythemia-stressing-out-the-megakaryocyte-nucleus
#14
Francisco Jose Iborra, Petros Papadopoulos
Calreticulin (CALR) is a multifaceted protein primarily involved in intracellular protein control processes. The identification of CALR mutations in essential thrombocythemia (ET) and primary myelofibrosis that are mutually exclusive with the JAK2 V617F mutation has stirred an intensive research interest about the molecular functions of CALR and its mutants in myeloproliferative neoplasms (MPNs) and its diagnostic/prognostic value. The recently characterized protein-protein interaction of CALR mutants and MPL receptor has advanced our knowledge on the functional role of CALR mutants in thrombocythemia but it has also uncovered limitations of the current established research models...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28584094/reconstructing-blood-stem-cell-regulatory-network-models-from-single-cell-molecular-profiles
#15
Fiona K Hamey, Sonia Nestorowa, Sarah J Kinston, David G Kent, Nicola K Wilson, Berthold Göttgens
Adult blood contains a mixture of mature cell types, each with specialized functions. Single hematopoietic stem cells (HSCs) have been functionally shown to generate all mature cell types for the lifetime of the organism. Differentiation of HSCs toward alternative lineages must be balanced at the population level by the fate decisions made by individual cells. Transcription factors play a key role in regulating these decisions and operate within organized regulatory programs that can be modeled as transcriptional regulatory networks...
June 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28571745/acetylation-of-mkl1-by-pcaf-regulates-pro-inflammatory-transcription
#16
Liming Yu, Zilong Li, Mingming Fang, Yong Xu
Inflammation is considered a fundamental host defense mechanism and, when aberrantly activated, contributes to a host of human diseases. Previously we have reported that the transcriptional regulator megakaryocytic leukemia 1 (MKL1) plays a role programming cellular inflammatory response by modulating NF-κB activity. Here we report that MKL1 was acetylated in vivo and pro-inflammatory stimuli (TNF-α and LPS) augmented MKL1 acetylation accompanying increased MKL1 binding to NF-κB target promoters. Further analysis revealed that the lysine acetyltransferase PCAF mediated MKL1 acetylation: TNF-α and LPS promoted the interaction between MKL1 and PCAF whereas depletion of PCAF abrogated the induction of MKL1 acetylation by TNF-α and LPS...
May 30, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28570310/terminal-maturation-of-orthochromatic-erythroblasts-is-impaired-in-burn-patients
#17
Shirin Hasan, Michael J Mosier, Peggie Conrad, Andrea Szilagyi, Richard L Gamelli, Kuzhali Muthumalaiappan
Mechanisms of erythropoietin (Epo)-resistant anemia in burn patients are poorly understood. We have recently found that administering a nonselective beta 1,2-adrenergic blocker propranolol (PR) was effective in reversing myelo-erythroid commitment through MafB regulation and increase megakaryocyte erythrocyte progenitors in burn patients' PBMC-derived ex vivo culture system. Having known that Epo-dependent proliferation of early erythroblasts is intact after burn injury, here we inquired whether or not Epo-independent maturation stage of erythropoiesis is affected by burn injury and the relative role of PR on late-stage erythropoiesis...
May 30, 2017: Journal of Burn Care & Research: Official Publication of the American Burn Association
https://www.readbyqxmd.com/read/28569613/the-role-of-bone-marrow-microenvironment-in-platelet-production-and-their-implications-for-the-treatment-of-thrombocytopenic-diseases
#18
Jun-Ying Wang, Shuang Ye, Hua Zhong
OBJECTIVES: Impaired platelet production has been found to be an important pathological mechanism of thrombocytopenia in many diseases. Platelet generation is a complex process that mainly occurs in the bone marrow, and thus is closely regulated by the bone marrow microenvironment. This review attempts to summarize the most current knowledge referring the role of bone marrow microenvironment in the regulation of platelet production. METHODS: The effects of multiple microenvironment ingredients in regulating megakaryopoiesis and thrombocytopoiesis have been discussed...
June 1, 2017: Hematology (Amsterdam, Netherlands)
https://www.readbyqxmd.com/read/28566565/gata-transcription-factors-basic-principles-and-related-human-disorders
#19
Tohru Fujiwara
The development of mature blood cell from hematopoietic stem cells is regulated by transcription factors that coordinate the expression of lineage-specific genes. GATA transcription factors are zinc finger DNA-binding proteins that play crucial roles in various biological processes, including hematopoiesis. Among GATA family proteins, GATA-1, GATA-2, and GATA-3 are essential for hematopoiesis. GATA-1 functions to promote development of erythrocytes, megakaryocytes, eosinophils, and mast cells. Mutations in GATA-1 are associated with acute megakaryoblastic leukemia (AMKL), congenital erythroid hypoplasia (Diamond-Blackfan anemia; DBA), and X-linked anemia and/or thrombocytopenia...
2017: Tohoku Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28548028/developmental-differences-between-newborn-and-adult-mice-in-response-to-romiplostim
#20
Katherine A Sparger, Haley Ramsey, Viola Lorenz, Zhi-Jian Liu, Henry A Feldman, Nan Li, Tahirih Laforest, Martha C Sola-Visner
Thrombocytopenia is frequent among sick neonates. While most cases are transient, some neonates experience prolonged and severe thrombocytopenia. These infants often pose diagnostic and therapeutic challenges, and may receive large numbers of platelet transfusions. Romiplostim (ROM) is a thrombopoietin (TPO)-receptor-agonist approved for treatment of adults with chronic immune thrombocytopenia (ITP). The immature platelet fraction (IPF) is a novel measure of newly produced platelets, which could aid with the diagnostic evaluation of thrombocytopenic neonates...
May 26, 2017: Platelets
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