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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
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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)...
July 27, 2016: Platelets
https://www.readbyqxmd.com/read/27450272/transcription-factor-defects-causing-platelet-disorders
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
https://www.readbyqxmd.com/read/26721389/conbind-motif-aware-cross-species-alignment-for-the-identification-of-functional-transcription-factor-binding-sites
#17
Stefan H Lelieveld, Judith Schütte, Maurits J J Dijkstra, Punto Bawono, Sarah J Kinston, Berthold Göttgens, Jaap Heringa, Nicola Bonzanni
Eukaryotic gene expression is regulated by transcription factors (TFs) binding to promoter as well as distal enhancers. TFs recognize short, but specific binding sites (TFBSs) that are located within the promoter and enhancer regions. Functionally relevant TFBSs are often highly conserved during evolution leaving a strong phylogenetic signal. While multiple sequence alignment (MSA) is a potent tool to detect the phylogenetic signal, the current MSA implementations are optimized to align the maximum number of identical nucleotides...
May 5, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/26619147/gfi1-proteins-orchestrate-the-emergence-of-haematopoietic-stem-cells-through-recruitment-of-lsd1
#18
Roshana Thambyrajah, Milena Mazan, Rahima Patel, Victoria Moignard, Monika Stefanska, Elli Marinopoulou, Yaoyong Li, Christophe Lancrin, Thomas Clapes, Tarik Möröy, Catherine Robin, Crispin Miller, Shaun Cowley, Berthold Göttgens, Valerie Kouskoff, Georges Lacaud
In vertebrates, the first haematopoietic stem cells (HSCs) with multi-lineage and long-term repopulating potential arise in the AGM (aorta-gonad-mesonephros) region. These HSCs are generated from a rare and transient subset of endothelial cells, called haemogenic endothelium (HE), through an endothelial-to-haematopoietic transition (EHT). Here, we establish the absolute requirement of the transcriptional repressors GFI1 and GFI1B (growth factor independence 1 and 1B) in this unique trans-differentiation process...
January 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/26447191/from-cytopenia-to-leukemia-the-role-of-gfi1-and-gfi1b-in-blood-formation
#19
REVIEW
Tarik Möröy, Lothar Vassen, Brian Wilkes, Cyrus Khandanpour
The DNA-binding zinc finger transcription factors Gfi1 and Gfi1b were discovered more than 20 years ago and are recognized today as major regulators of both early hematopoiesis and hematopoietic stem cells. Both proteins function as transcriptional repressors by recruiting histone-modifying enzymes to promoters and enhancers of target genes. The establishment of Gfi1 and Gfi1b reporter mice made it possible to visualize their cell type-specific expression and to understand their function in hematopoietic lineages...
December 10, 2015: Blood
https://www.readbyqxmd.com/read/26380221/disseminated-medulloblastoma-in-a-child-with-germline-brca2-6174delt-mutation-and-without-fanconi-anemia
#20
Jingying Xu, Ashley Sloane Margol, Anju Shukla, Xiuhai Ren, Jonathan L Finlay, Mark D Krieger, Floyd H Gilles, Fergus J Couch, Meraj Aziz, Eric T Fung, Shahab Asgharzadeh, Michael T Barrett, Anat Erdreich-Epstein
Medulloblastoma, the most common malignant brain tumor in children, occurs with increased frequency in individuals with Fanconi anemia who have biallelic germline mutations in BRCA2. We describe an 8-year-old child who had disseminated anaplastic medulloblastoma and a deleterious heterozygous BRCA2 6174delT germline mutation. Molecular profiling was consistent with Group 4 medulloblastoma. The posterior fossa mass was resected and the patient received intensive chemotherapy and craniospinal irradiation. Despite this, the patient succumbed to a second recurrence of his medulloblastoma, which presented 8 months after diagnosis as malignant pleural and peritoneal effusions...
2015: Frontiers in Oncology
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