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https://www.readbyqxmd.com/read/28096094/platelet-cd34-expression-and-%C3%AE-%C3%AE-granule-abnormalities-in-gfi1b-and-runx1-related-familial-bleeding-disorders
#1
Anna E Marneth, Waander L van Heerde, Konnie M Hebeda, Britta A P Laros-van Gorkom, Wideke Barteling, Brigith Willemsen, Aniek O de Graaf, Annet Simons, Joop H Jansen, Frank Preijers, Marjolijn C Jongmans, Bert A van der Reijden
No abstract text is available yet for this article.
January 17, 2017: Blood
https://www.readbyqxmd.com/read/28060340/reprogramming-mouse-embryonic-fibroblasts-with-transcription-factors-to-induce-a-hemogenic-program
#2
Michael G Daniel, Carlos-Filipe Pereira, Jeffrey M Bernitz, Ihor R Lemischka, Kateri Moore
This protocol details the induction of a hemogenic program in mouse embryonic fibroblasts (MEFs) via overexpression of transcription factors (TFs). We first designed a reporter screen using MEFs from human CD34-tTA/TetO-H2BGFP (34/H2BGFP) double transgenic mice. CD34(+) cells from these mice label H2B histones with GFP, and cease labeling upon addition of doxycycline (DOX). MEFS were transduced with candidate TFs and then observed for the emergence of GFP(+) cells that would indicate the acquisition of a hematopoietic or endothelial cell fate...
December 16, 2016: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28056107/autophagy-is-an-innate-mechanism-associated-with-leprosy-polarization
#3
Bruno Jorge de Andrade Silva, Mayara Garcia de Mattos Barbosa, Priscila Ribeiro Andrade, Helen Ferreira, José Augusto da Costa Nery, Suzana Côrte-Real, Gilberto Marcelo Sperandio da Silva, Patricia Sammarco Rosa, Mario Fabri, Euzenir Nunes Sarno, Roberta Olmo Pinheiro
Leprosy is a chronic infectious disease that may present different clinical forms according to the immune response of the host. Levels of IFN-γ are significantly raised in paucibacillary tuberculoid (T-lep) when compared with multibacillary lepromatous (L-lep) patients. IFN-γ primes macrophages for inflammatory activation and induces the autophagy antimicrobial mechanism. The involvement of autophagy in the immune response against Mycobacterium leprae remains unexplored. Here, we demonstrated by different autophagic assays that LC3-positive autophagosomes were predominantly observed in T-lep when compared with L-lep lesions and skin-derived macrophages...
January 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28041820/combined-alpha-delta-platelet-storage-pool-deficiency-is-associated-with-mutations-in-gfi1b
#4
Carlos R Ferreira, Dong Chen, Shirley M Abraham, David R Adams, Karen L Simon, May C Malicdan, Thomas C Markello, Meral Gunay-Aygun, William A Gahl
Combined alpha-delta platelet storage pool deficiency is characterized by the absence or reduction in the number of both alpha granules and dense bodies. This disorder can have variable severity as well as a variable inheritance pattern. We describe two patients from unrelated families with combined alpha-delta storage pool deficiency due to mutations in GFI1B, a zinc finger protein known to act as a transcriptional repressor of various genes. We demonstrate that this disease is associated with either a heterozygous mutation (de novo or familial) abrogating the binding of the zinc fingers with the promoter of its target genes, or by hypomorphic biallelic mutations in GFI1B leading to autosomal recessive inheritance...
December 18, 2016: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/27903753/a-novel-lsd1-inhibitor-t-3775440-disrupts-gfi1b-containing-complex-leading-to-transdifferentiation-and-impaired-growth-of-aml-cells
#5
Yoshinori Ishikawa, Kanae Gamo, Masato Yabuki, Shinji Takagi, Kosei Toyoshima, Kazuhide Nakayama, Akiko Nakayama, Megumi Morimoto, Hitoshi Miyashita, Ryo Dairiki, Yukiko Hikichi, Naoki Tomita, Daisuke Tomita, Shinichi Imamura, Misa Iwatani, Yusuke Kamada, Satoru Matsumoto, Ryujiro Hara, Toshiyuki Nomura, Ken Tsuchida, Kazuhide Nakamura
Dysregulation of the histone demethylase LSD1, also known as KDM1A, has been implicated in the development of various cancers, including leukemia. Here we describe the anti-leukemic activity and mechanism of action of T-3775440, a novel irreversible LSD1 inhibitor. Cell growth analysis of leukemia cell lines revealed that acute erythroleukemia (AEL) and acute megakaryoblastic leukemia cells (AMKL) were highly sensitive to this compound. T-3775440 treatment enforced transdifferentiation of erythroid/megakaryocytic lineages into granulomonocytic-like lineage cells...
November 30, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27768697/cooperative-stimulation-of-megakaryocytic-differentiation-by-gfi1b-gene-targets-kindlin3-and-talin1
#6
Divya Singh, Ghanshyam Upadhyay, Ananya Sengupta, Mohammed A Biplob, Shaleen Chakyayil, Tiji George, Shireen Saleque
Understanding the production and differentiation of megakaryocytes from progenitors is crucial for realizing the biology and functions of these vital cells. Previous gene ablation studies demonstrated the essential role of the transcriptional repressor Gfi1b (growth factor independence 1b) in the generation of both erythroid and megakaryocytic cells. However, our recent work has demonstrated the down-regulation of this factor during megakaryocytic differentiation. In this study we identify two new gene targets of Gfi1b, the cytoskeletal proteins Kindlin3 and Talin1, and demonstrate the inverse expression and functions of these cytoskeletal targets relative to Gfi1b, during megakaryocytic differentiation...
2016: PloS One
https://www.readbyqxmd.com/read/27588453/whole-exome-sequencing-identifies-loci-associated-with-blood-cell-traits-and-reveals-a-role-for-alternative-gfi1b-splice-variants-in-human-hematopoiesis
#7
Linda M Polfus, Rajiv K Khajuria, Ursula M Schick, Nathan Pankratz, Raha Pazoki, Jennifer A Brody, Ming-Huei Chen, Paul L Auer, James S Floyd, Jie Huang, Leslie Lange, Frank J A van Rooij, Richard A Gibbs, Ginger Metcalf, Donna Muzny, Narayanan Veeraraghavan, Klaudia Walter, Lu Chen, Lisa Yanek, Lewis C Becker, Gina M Peloso, Aoi Wakabayashi, Mart Kals, Andres Metspalu, Tõnu Esko, Keolu Fox, Robert Wallace, Nora Franceschini, Nena Matijevic, Kenneth M Rice, Traci M Bartz, Leo-Pekka Lyytikäinen, Mika Kähönen, Terho Lehtimäki, Olli T Raitakari, Ruifang Li-Gao, Dennis O Mook-Kanamori, Guillaume Lettre, Cornelia M van Duijn, Oscar H Franco, Stephen S Rich, Fernando Rivadeneira, Albert Hofman, André G Uitterlinden, James G Wilson, Bruce M Psaty, Nicole Soranzo, Abbas Dehghan, Eric Boerwinkle, Xiaoling Zhang, Andrew D Johnson, Christopher J O'Donnell, Jill M Johnsen, Alexander P Reiner, Santhi K Ganesh, Vijay G Sankaran
No abstract text is available yet for this article.
September 1, 2016: American Journal of Human Genetics
https://www.readbyqxmd.com/read/27486782/whole-exome-sequencing-identifies-loci-associated-with-blood-cell-traits-and-reveals-a-role-for-alternative-gfi1b-splice-variants-in-human-hematopoiesis
#8
Linda M Polfus, Rajiv K Khajuria, Ursula M Schick, Nathan Pankratz, Raha Pazoki, Jennifer A Brody, Ming-Huei Chen, Paul L Auer, James S Floyd, Jie Huang, Leslie Lange, Frank J A van Rooij, Richard A Gibbs, Ginger Metcalf, Donna Muzny, Narayanan Veeraraghavan, Klaudia Walter, Lu Chen, Lisa Yanek, Lewis C Becker, Gina M Peloso, Aoi Wakabayashi, Mart Kals, Andres Metspalu, Tõnu Esko, Keolu Fox, Robert Wallace, Nora Franceshini, Nena Matijevic, Kenneth M Rice, Traci M Bartz, Leo-Pekka Lyytikäinen, Mika Kähönen, Terho Lehtimäki, Olli T Raitakari, Ruifang Li-Gao, Dennis O Mook-Kanamori, Guillaume Lettre, Cornelia M van Duijn, Oscar H Franco, Stephen S Rich, Fernando Rivadeneira, Albert Hofman, André G Uitterlinden, James G Wilson, Bruce M Psaty, Nicole Soranzo, Abbas Dehghan, Eric Boerwinkle, Xiaoling Zhang, Andrew D Johnson, Christopher J O'Donnell, Jill M Johnsen, Alexander P Reiner, Santhi K Ganesh, Vijay G Sankaran
Circulating blood cell counts and indices are important indicators of hematopoietic function and a number of clinical parameters, such as blood oxygen-carrying capacity, inflammation, and hemostasis. By performing whole-exome sequence association analyses of hematologic quantitative traits in 15,459 community-dwelling individuals, followed by in silico replication in up to 52,024 independent samples, we identified two previously undescribed coding variants associated with lower platelet count: a common missense variant in CPS1 (rs1047891, MAF = 0...
August 4, 2016: American Journal of Human Genetics
https://www.readbyqxmd.com/read/27471498/protective-vaccination-against-blood-stage-malaria-of-plasmodium-chabaudi-differential-gene-expression-in-the-liver-of-balb-c-mice-toward-the-end-of-crisis-phase
#9
Saleh A Al-Quraishy, Mohamed A Dkhil, Abdel-Azeem A Abdel-Baki, Denis Delic, Frank Wunderlich
Protective vaccination induces self-healing of otherwise fatal blood-stage malaria of Plasmodium chabaudi in female Balb/c mice. To trace processes critically involved in self-healing, the liver, an effector against blood-stage malaria, is analyzed for possible changes of its transcriptome in vaccination-protected in comparison to non-protected mice toward the end of the crisis phase. Gene expression microarray analyses reveal that vaccination does not affect constitutive expression of mRNA and lincRNA. However, malaria induces significant (p < 0...
2016: Frontiers in Microbiology
https://www.readbyqxmd.com/read/27463948/inherited-platelet-dysfunction-and-hematopoietic-transcription-factor-mutations
#10
Natthapol Songdej, A Koneti Rao
Transcription factors (TFs) are proteins that bind to specific DNA sequences and regulate expression of genes. The molecular and genetic mechanisms in most patients with inherited platelet dysfunction are unknown. There is now increasing evidence that mutations in hematopoietic TFs are an important underlying cause for the defects in platelet production, morphology, and function. The hematopoietic TFs implicated in the patients with impaired platelet function include Runt related TF 1 (RUNX1), Fli-1 proto-oncogene, ETS TF (FLI1), GATA-binding protein 1 (GATA1), and growth factor independent 1B transcriptional repressor (GFI1B)...
January 2017: Platelets
https://www.readbyqxmd.com/read/27450272/transcription-factor-defects-causing-platelet-disorders
#11
Martina E Daly
Recent years have seen increasing recognition of a subgroup of inherited platelet function disorders which are due to defects in transcription factors that are required to regulate megakaryopoiesis and platelet production. Thus, germline mutations in the genes encoding the haematopoietic transcription factors RUNX1, GATA-1, FLI1, GFI1b and ETV6 have been associated with both quantitative and qualitative platelet abnormalities, and variable bleeding symptoms in the affected patients. Some of the transcription factor defects are also associated with an increased predisposition to haematologic malignancies (RUNX1, ETV6), abnormal erythropoiesis (GATA-1, GFI1b, ETV6) and immune dysfunction (FLI1)...
July 16, 2016: Blood Reviews
https://www.readbyqxmd.com/read/27443289/cbf%C3%AE-smmhc-creates-aberrant-megakaryocyte-erythroid-progenitors-prone-to-leukemia-initiation-in-mice
#12
Qi Cai, Robin Jeannet, Wei-Kai Hua, Guerry J Cook, Bin Zhang, Jing Qi, Hongjun Liu, Ling Li, Ching-Cheng Chen, Guido Marcucci, Ya-Huei Kuo
Acute myeloid leukemia (AML) arises through multistep clonal evolution characterized by stepwise accumulation of successive alterations affecting the homeostasis of differentiation, proliferation, self-renewal, and survival programs. The persistence and dynamic clonal evolution of leukemia-initiating cells and preleukemic stem cells during disease progression and treatment are thought to contribute to disease relapse and poor outcome. Inv(16)(p13q22) or t(16;16)(p13.1;q22), one of the most common cytogenetic abnormalities in AML, leads to expression of a fusion protein CBFβ-SMMHC (CM) known to disrupt myeloid and lymphoid differentiation...
September 15, 2016: Blood
https://www.readbyqxmd.com/read/27432513/a-gene-trap-transposon-eliminates-haematopoietic-expression-of-zebrafish-gfi1aa-but-does-not-interfere-with-haematopoiesis
#13
Roshana Thambyrajah, Deniz Ucanok, Maryam Jalali, Yasmin Hough, Robert Neil Wilkinson, Kathryn McMahon, Chris Moore, Martin Gering
A transposon-mediated gene trap screen identified the zebrafish line qmc551 that expresses a GFP reporter in primitive erythrocytes and also in haemogenic endothelial cells, which give rise to haematopoietic stem and progenitor cells (HSPCs) that seed sites of larval and adult haematopoiesis. The transposon that mediates this GFP expression is located in intron 1 of the gfi1aa gene, one of three zebrafish paralogs that encode transcriptional repressors homologous to mammalian Gfi1 and Gfi1b proteins. In qmc551 transgenics, GFP expression is under the control of the endogenous gfi1aa promoter, recapitulates early gfi1aa expression and allows live observation of gfi1aa promoter activity...
September 1, 2016: Developmental Biology
https://www.readbyqxmd.com/read/27399214/new-insights-into-the-regulation-by-runx1-and-gfi1-s-proteins-of-the-endothelial-to-hematopoietic-transition-generating-primordial-hematopoietic-cells
#14
Roshana Thambyrajah, Rahima Patel, Milena Mazan, Michael Lie-A-Ling, Andrew J Lilly, Alexia Eliades, Sara Menegatti, Eva Garcia-Alegria, Magdalena Florkowska, Kiran Batta, Valerie Kouskoff, Georges Lacaud
The first hematopoietic cells are generated very early in ontogeny to support the growth of the embryo and to provide the foundation to the adult hematopoietic system. There is a considerable therapeutic interest in understanding how these first blood cells are generated in order to try to reproduce this process in vitro. This would allow to generate at will blood products or hematopoietic cell populations from embryonic stem cells (ESCs), induced pluripotent stem cells or through directed reprogramming. Recent studies have clearly established that the first hematopoietic cells originate from a hemogenic endothelium (HE) through an endothelial to hematopoietic transition (EHT)...
July 11, 2016: Cell Cycle
https://www.readbyqxmd.com/read/27365426/germ-line-variants-predispose-to-both-jak2-v617f-clonal-hematopoiesis-and-myeloproliferative-neoplasms
#15
David A Hinds, Kimberly E Barnholt, Ruben A Mesa, Amy K Kiefer, Chuong B Do, Nicholas Eriksson, Joanna L Mountain, Uta Francke, Joyce Y Tung, Huong Marie Nguyen, Haiyu Zhang, Linda Gojenola, James L Zehnder, Jason Gotlib
We conducted a genome-wide association study (GWAS) to identify novel predisposition alleles associated with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) and JAK2 V617F clonal hematopoiesis in the general population. We recruited a web-based cohort of 726 individuals with polycythemia vera, essential thrombocythemia, and myelofibrosis and 252 637 population controls unselected for hematologic phenotypes. Using a single-nucleotide polymorphism (SNP) array platform with custom probes for the JAK2 V617F mutation (V617F), we identified 497 individuals (0...
August 25, 2016: Blood
https://www.readbyqxmd.com/read/27151440/prdm16-suppresses-mll1r-leukemia-via-intrinsic-histone-methyltransferase-activity
#16
Bo Zhou, Jingya Wang, Shirley Y Lee, Jie Xiong, Natarajan Bhanu, Qi Guo, Peilin Ma, Yuqing Sun, Rajesh C Rao, Benjamin A Garcia, Jay L Hess, Yali Dou
PRDM16 is a transcription co-factor that plays critical roles in development of brown adipose tissue, as well as maintenance of adult hematopoietic and neural stem cells. Here we report that PRDM16 is a histone H3K4 methyltransferase on chromatin. Mutation in the N-terminal PR domain of PRDM16 abolishes the intrinsic enzymatic activity of PRDM16. We show that the methyltransferase activity of PRDM16 is required for specific suppression of MLL fusion protein-induced leukemogenesis both in vitro and in vivo...
April 12, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27122003/functional-characterization-of-a-novel-gfi1b-mutation-causing-congenital-macrothrombocytopenia
#17
K Kitamura, Y Okuno, K Yoshida, M Sanada, Y Shiraishi, H Muramatsu, R Kobayashi, K Furukawa, S Miyano, S Kojima, S Ogawa, S Kunishima
UNLABELLED: Essentials Two groups recently reported GFI1B as a novel causative gene for congenital macrothrombocytopenia. We performed functional analysis of a novel GFI1B mutation and previous mutations. An immunofluorescence analysis of the platelet CD34 expression can be useful as a screening test. Mutant-transduced megakaryocytes produced enlarged proplatelet tips which were reduced in number. SUMMARY: Background GFI1B is an essential transcription factor for megakaryocyte and erythrocyte development...
July 2016: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/26971401/should-any-genetic-defect-affecting-%C3%AE-granules-in-platelets-be-classified-as-gray-platelet-syndrome
#18
Alan T Nurden, Paquita Nurden
There is much current interest in the role of the platelet storage pool of α-granule proteins both in hemostasis and non-hemostatic events. As well as in the arrest of bleeding, the secreted proteins participate in wound healing, inflammation, and innate immunity while in pathology they may be actors in arterial thrombosis and atherosclerosis as well as cancer and metastasis. For a long time, gray platelet syndrome (GPS) has been regarded as the classic inherited platelet disorder caused by an absence of α-granules and their contents...
July 2016: American Journal of Hematology
https://www.readbyqxmd.com/read/26951200/sumoylation-regulates-growth-factor-independence-1-in-transcriptional-control-and-hematopoiesis
#19
Daniel Andrade, Matthew Velinder, Jason Singer, Luke Maese, Diana Bareyan, Hong Nguyen, Mahesh B Chandrasekharan, Helena Lucente, David McClellan, David Jones, Sunil Sharma, Fang Liu, Michael E Engel
Cell fate specification requires precise coordination of transcription factors and their regulators to achieve fidelity and flexibility in lineage allocation. The transcriptional repressor growth factor independence 1 (GFI1) is comprised of conserved Snail/Slug/Gfi1 (SNAG) and zinc finger motifs separated by a linker region poorly conserved with GFI1B, its closest homolog. Moreover, GFI1 and GFI1B coordinate distinct developmental fates in hematopoiesis, suggesting that their functional differences may derive from structures within their linkers...
May 15, 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/26851695/a-somatic-mutation-of-gfi1b-identified-in-leukemia-alters-cell-fate-via-a-spi1-pu-1-centered-genetic-regulatory-network
#20
Eduardo Anguita, Rajeev Gupta, Victor Olariu, Peter J Valk, Carsten Peterson, Ruud Delwel, Tariq Enver
We identify a mutation (D262N) in the erythroid-affiliated transcriptional repressor GFI1B, in an acute myeloid leukemia (AML) patient with antecedent myelodysplastic syndrome (MDS). The GFI1B-D262N mutant functionally antagonizes the transcriptional activity of wild-type GFI1B. GFI1B-D262N promoted myelomonocytic versus erythroid output from primary human hematopoietic precursors and enhanced cell survival of both normal and MDS derived precursors. Re-analysis of AML transcriptome data identifies a distinct group of patients in whom expression of wild-type GFI1B and SPI1 (PU...
March 15, 2016: Developmental Biology
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