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https://www.readbyqxmd.com/read/28060419/a-molecular-roadmap-of-definitive-erythropoiesis-from-human-induced-pluripotent-stem-cells
#1
Muhammad A Razaq, Stephen Taylor, David J Roberts, Lee Carpenter
Human induced pluripotent stem cells (hiPSCs) are being considered for use in understanding haematopoietic disorders and as a potential source of in vitro manufactured red cells. Here, we show that hiPSCs are able to recapitulate various stages of developmental erythropoiesis. We show that primitive erythroblasts arise first, express CD31(+) with CD235a(+) , embryonic globins and red cell markers, but fail to express the hallmark red cell transcripts of adult erythropoiesis. When hiPSC-derived CD45(+) CD235a(-) haematopoietic progenitors are isolated on day 12 and further differentiated on OP9 stroma, they selectively express CD36(+) and CD235a(+) , adult erythroid transcripts for transcription factors (e...
January 6, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28053695/study-on-hydroxyurea-response-in-hemoglobinopathies-patients-using-genetic-markers-and-liquid-erythroid-cultures
#2
Serena Sclafani, Alice Pecoraro, Veronica Agrigento, Antonio Troia, Rosario Di Maggio, Massimiliano Sacco, Aurelio Maggio, Elena D'Alcamo, Rosalba Di Marzo
Increased expression of fetal hemoglobin (HbF) may ameliorate the clinical course of hemoglobinopathies. Hydroxyurea (HU) is the only inducer approved for the treatment of these diseases able to stimulate HbF production but patients' response is highly variable indicating the utility of the identification of pharmacogenomic biomarkers in order to predict pharmacological treatment efficacy. To date few studies to evaluate the role of genetic determinants in HU response have been conducted showing contradictory results...
November 2, 2016: Hematology Reports
https://www.readbyqxmd.com/read/27909215/cure-for-thalassemia-major-from-allogeneic-hematopoietic-stem-cell-transplantation-to-gene-therapy
#3
Alok Srivastava, Ramachandran V Shaji
Allogeneic hematopoietic stem cell transplantation has been established for several decades as a gene replacement therapy for patients with thalassemia major and now offers very high rates of cure to those who are able to access this therapy. Outcomes have improved tremendously over the last decade even in high-risk patients. The limited data available suggests that the long-term outcome is also excellent with >90% survival but for best results, hematopoietic stem cell transplantation should be offered early before any end organ damage occurs...
December 1, 2016: Haematologica
https://www.readbyqxmd.com/read/27884397/corrigendum-to-bcl11a-expression-in-acute-phase-chronic-myeloid-leukemia-leuk-res-47-2016-88-92
#4
Jiawei Yin, Fan Zhang, Huiquan Tao, Xiao Ma, Guangsong Su, Xiaoli Xie, Zhongjuan Xu, Yanwen Zheng, Hong Liu, Chao He, Zhengwei Jenny Mao, Zhiwei Wang, Weirong Chang, Robert Peter Gale, Depei Wu, Bin Yin
No abstract text is available yet for this article.
January 2017: Leukemia Research
https://www.readbyqxmd.com/read/27872702/gamma-reactivation-using-the-spongy-effect-of-klf1-binding-site-sequence-an-approach-in-gene-therapy-for-beta-thalassemia
#5
Nasrin Heydari, Laleh Shariati, Hossein Khanahmad, Zahra Hejazi, Mansoureh Shahbazi, Mansoor Salehi
OBJECTIVES: β-thalassemia is one of the most common genetic disorders in the world. As one of the promising treatment strategies, fetal hemoglobin (Hb F) can be induced. The present study was an attempt to reactivate the γ-globin gene by introducing a gene construct containing KLF1 binding sites to the K562 cell line. MATERIALS AND METHODS: A plasmid containing a 192 bp sequence with two repeats of KLF1 binding sites on β-globin and BCL11A promoters was constructed and used to transfect the K562 cell line...
October 2016: Iranian Journal of Basic Medical Sciences
https://www.readbyqxmd.com/read/27861570/hmga2-moderately-increases-fetal-hemoglobin-expression-in-human-adult-erythroblasts
#6
Jaira F de Vasconcellos, Y Terry Lee, Colleen Byrnes, Laxminath Tumburu, Antoinette Rabel, Jeffery L Miller
Induction of fetal hemoglobin (HbF) has therapeutic importance for patients with beta-hemoglobin disorders. Previous studies showed that let-7 microRNAs (miRNAs) are highly regulated in erythroid cells during the fetal-to-adult developmental transition, and that targeting let-7 mediated the up-regulation of HbF to greater than 30% of the total globin levels in human adult cultured erythroblasts. HMGA2 is a member of the high-mobility group A family of proteins and a validated target of the let-7 family of miRNAs...
2016: PloS One
https://www.readbyqxmd.com/read/27835906/whole-exome-and-transcriptome-sequencing-of-refractory-diffuse-large-b-cell-lymphoma
#7
Ha Young Park, Seung-Bok Lee, Hae-Yong Yoo, Seok-Jin Kim, Won-Seog Kim, Jong-Il Kim, Young-Hyeh Ko
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Although rituximab therapy improves clinical outcome, some patients develop resistant DLBCL; however, the genetic alterations in these patients are not well documented. To identify the genetic background of refractory DLBCL, we conducted whole-exome sequencing and transcriptome sequencing for six patients with refractory and seven with responsive DLBCL. The average numbers of pathogenic somatic single nucleotide variants and indels in coding regions were 71 in refractory patients (range 28-120) and 38 (range 19-66) in responsive patients...
November 9, 2016: Oncotarget
https://www.readbyqxmd.com/read/27786413/dna-methylation-profiling-of-pediatric-b-cell-lymphoblastic-leukemia-with-kmt2a-rearrangement-identifies-hypomethylation-at-enhancer-sites
#8
Anke K Bergmann, Giancarlo Castellano, Julia Alten, Ole Ammerpohl, Julia Kolarova, Jessica Nordlund, Jose Ignacio Martin-Subero, Martin Schrappe, Reiner Siebert
Deregulation of the epigenome is an important pathogenetic mechanism in acute lymphoblastic leukemia (ALL) with lysine (K)-specific methyltransferase 2A rearrangement (KMT2Ar). We performed array-based DNA methylation profiling of KMT2Ar ALL cells from 26 children in comparison to normal B-cell precursors. Significant changes in DNA methylation in KMT2Ar ALL were identified in 2,545 CpG loci, influenced by age and the translocation partners AFF1 and MLLT1. In KMT2Ar ALL, DNA methylation loss was enriched at enhancers and for certain transcription factor binding sites such as BCL11A, EBF, and MEF2A...
October 27, 2016: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/27782803/co-activator-candidate-interactions-for-orphan-nuclear-receptor-nr2e1
#9
Ximena Corso-Díaz, Charles N de Leeuw, Vivian Alonso, Diana Melchers, Bibiana K Y Wong, René Houtman, Elizabeth M Simpson
BACKGROUND: NR2E1 (Tlx) is an orphan nuclear receptor that regulates the maintenance and self-renewal of neural stem cells, and promotes tumourigenesis. Nr2e1-null mice exhibit reduced cortical and limbic structures and pronounced retinal dystrophy. NR2E1 functions mainly as a repressor of gene transcription in association with the co-repressors atrophin-1, LSD1, HDAC and BCL11A. Recent evidence suggests that NR2E1 also acts as an activator of gene transcription. However, co-activator complexes that interact with NR2E1 have not yet been identified...
October 26, 2016: BMC Genomics
https://www.readbyqxmd.com/read/27774950/-knock-down-of-bcl11a-expression-in-breast-cancer-cells-promotes-mda-mb-231-cell-apoptosis
#10
Hongli Li, Chen Gui, Lijun Yan
Objective To detect the expression and pathological significance of B-cell CLL/lymphoma 11A (BCL11A) in breast cancer and investigate the effect of its silencing on the apoptosis of human MDA-MB-231 breast cancer cells. MethodsImmunohistochemistry was used to detect the expression of BCL11A in 62 cases of human breast cancer tissues and 8 cases of normal tissues. We synthesized siRNA targeting BCL11A, and then siRNA was transfected into MDA-MB-231 cells. Forty-eight hours later, the suppression effect of siRNA on BCL11A was determined by quantitative real-time PCR and Western blotting...
November 2016: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
https://www.readbyqxmd.com/read/27769165/distinct-gene-expression-program-dynamics-during-erythropoiesis-from-human-induced-pluripotent-stem-cells-compared-with-adult-and-cord-blood-progenitors
#11
Alison T Merryweather-Clarke, Alex J Tipping, Abigail A Lamikanra, Rui Fa, Basel Abu-Jamous, Hoi Pat Tsang, Lee Carpenter, Kathryn J H Robson, Asoke K Nandi, David J Roberts
BACKGROUND: Human-induced pluripotent stem cells (hiPSCs) are a potentially invaluable resource for regenerative medicine, including the in vitro manufacture of blood products. HiPSC-derived red blood cells are an attractive therapeutic option in hematology, yet exhibit unexplained proliferation and enucleation defects that presently preclude such applications. We hypothesised that substantial differential regulation of gene expression during erythroid development accounts for these important differences between hiPSC-derived cells and those from adult or cord-blood progenitors...
October 21, 2016: BMC Genomics
https://www.readbyqxmd.com/read/27710960/molecular-understanding-of-non-transfusion-dependent-thalassemia-associated-with-hemoglobin-e-%C3%AE-thalassemia-in-northeast-thailand
#12
Supawadee Yamsri, Naruwat Pakdee, Goonnapa Fucharoen, Kanokwan Sanchaisuriya, Supan Fucharoen
Non-transfusion-dependent thalassemia (NTDT) is associated with various forms of thalassemia and genetic modifiers. We report the molecular basis of NTDT in hemoglobin (Hb) E-β-thalassemia disease. This study was done in 73 adult patients encountered at the prenatal diagnosis center of Khon Kaen University, Northeast Thailand. Hematological parameters and Hb patterns were collected, and α- and β-globin gene mutations were determined. Multiple single-nucleotide polymorphisms (SNPs) including the rs7482144/Gγ-XmnI polymorphism, rs2297339, rs2838513, rs4895441, and rs9399137 in the HBS1L-MYB gene, rs4671393 and rs11886868 in the BCL11A gene, and G176AfsX179 in the KLF1 gene were examined...
2016: Acta Haematologica
https://www.readbyqxmd.com/read/27707736/strict-in-vivo-specificity-of-the-bcl11a-erythroid-enhancer
#13
Elenoe C Smith, Sidinh Luc, Donyell M Croney, Mollie B Woodworth, Luciano C Greig, Yuko Fujiwara, Minh Nguyen, Falak Sher, Jeffrey D Macklis, Daniel E Bauer, Stuart H Orkin
BCL11A, a repressor of human fetal (γ-)globin expression, is required for immune and hematopoietic stem cell functions and brain development. Regulatory sequences within the gene, which are subject to genetic variation affecting fetal globin expression, display hallmarks of an erythroid enhancer in cell lines and transgenic mice. As such this enhancer is a novel, attractive target for therapeutic gene editing. To explore the roles of such sequences in vivo, we generated mice in which the orthologous 10 kb intronic sequences were removed...
October 5, 2016: Blood
https://www.readbyqxmd.com/read/27707011/a-multi-locus-approach-to-characterization-of-major-quantitative-trait-loci-influencing-hb-f-regulation-in-chinese-%C3%AE-thalassemia-carriers
#14
Nelson C N Chan, Kin-Mang Lau, Kelvin C K Cheng, Natalie P H Chan, Margaret H L Ng
Genetic association studies showed that Hb F is under the influence of major quantitative trait loci (QTL) in β-thalassemia (β-thal) carriers. Single nucleotide polymorphisms (SNPs) at three major QTLs, BCL11A, HBS1L-MYB intergenic region and XmnI-HBG2, were individually validated in univariate models. However, their relative effect sizes on Hb F regulation are unknown. We genotyped 99 Chinese β-thal carriers for the three major QTLs and performed genetic association studies using three different statistical models, including mass univariate analysis, multivariate linear regression and partial least square regression structural equation modeling (PLS-SEM)...
October 5, 2016: Hemoglobin
https://www.readbyqxmd.com/read/27699255/identifying-candidate-genes-for-2p15p16-1-microdeletion-syndrome-using-clinical-genomic-and-functional-analysis
#15
Hani Bagheri, Chansonette Badduke, Ying Qiao, Rita Colnaghi, Iga Abramowicz, Diana Alcantara, Christopher Dunham, Jiadi Wen, Robert S Wildin, Malgorzata J M Nowaczyk, Jennifer Eichmeyer, Anna Lehman, Bruno Maranda, Sally Martell, Xianghong Shan, Suzanne M E Lewis, Mark O'Driscoll, Cheryl Y Gregory-Evans, Evica Rajcan-Separovic
The 2p15p16.1 microdeletion syndrome has a core phenotype consisting of intellectual disability, microcephaly, hypotonia, delayed growth, common craniofacial features, and digital anomalies. So far, more than 20 cases of 2p15p16.1 microdeletion syndrome have been reported in the literature; however, the size of the deletions and their breakpoints vary, making it difficult to identify the candidate genes. Recent reports pointed to 4 genes (XPO1, USP34, BCL11A, and REL) that were included, alone or in combination, in the smallest deletions causing the syndrome...
March 17, 2016: JCI Insight
https://www.readbyqxmd.com/read/27668420/genetic-disruption-of-the-klf1-gene-to-overexpress-gamma-globin-gene-using-crispr-cas9-system
#16
Laleh Shariati, Hossein Khanahmad, Mansoor Salehi, Zahra Hejazi, Ilnaz Rahimmaesh, Mohammad Amin Tabatabaiefar, Mohammad Hossein Modarressi
BACKGROUND: β-thalassemia is a major group of human genetic disorders which involves decrease or cease in the normal synthesis of the β-globin chains of hemoglobin. KLF1 is a key regulatory molecule involved in the γ to β-globin gene switching process directly inducing the expression of beta globin gene and indirectly repressing gamma globin. This study was performed to investigate the ability of an engineered CRISPR/Cas9 system to disrupt the KLF1 gene to inhibit the γ to β hemoglobin switching process in K562 cells...
September 26, 2016: Journal of Gene Medicine
https://www.readbyqxmd.com/read/27658436/apol1-%C3%AE-thalassemia-and-bcl11a-variants-as-a-genetic-risk-profile-for-progression-of-chronic-kidney-disease-in-sickle-cell-anemia
#17
LETTER
Santosh L Saraf, Binal N Shah, Xu Zhang, Jin Han, Bamidele O Tayo, Taimur Abbasi, Adam Ostrower, Elizabeth Guzman, Robert E Molokie, Michel Gowhari, Johara Hassan, Shivi Jain, Richard S Cooper, Roberto F Machado, James P Lash, Victor R Gordeuk
No abstract text is available yet for this article.
January 2017: Haematologica
https://www.readbyqxmd.com/read/27636225/an-expert-review-of-pharmacogenomics-of-sickle-cell-disease-therapeutics-not-yet-ready-for-global-precision-medicine
#18
Khuthala Mnika, Gift D Pule, Collet Dandara, Ambroise Wonkam
Sickle cell disease (SCD) is a blood disease caused by a single nucleotide substitution (T > A) in the beta globin gene on chromosome 11. The single point mutation (Glu6Val) promotes polymerization of hemoglobin S (HbS) and causes sickling of erythrocytes. Vaso-occlusive painful crises are associated with recurrent and long-term use of analgesics/opioids and hydroxyurea (HU) by people living with SCD. The present analysis offers a state-of-the-art expert review of the effectiveness of pharmacogenomics/genetics of pain management in SCD, with specific focus on HU and opioids...
October 2016: Omics: a Journal of Integrative Biology
https://www.readbyqxmd.com/read/27599293/lineage-specific-bcl11a-knockdown-circumvents-toxicities-and-reverses-sickle-phenotype
#19
Christian Brendel, Swaroopa Guda, Raffaele Renella, Daniel E Bauer, Matthew C Canver, Young-Jo Kim, Matthew M Heeney, Denise Klatt, Jonathan Fogel, Michael D Milsom, Stuart H Orkin, Richard I Gregory, David A Williams
Reducing expression of the fetal hemoglobin (HbF) repressor BCL11A leads to a simultaneous increase in γ-globin expression and reduction in β-globin expression. Thus, there is interest in targeting BCL11A as a treatment for β-hemoglobinopathies, including sickle cell disease (SCD) and β-thalassemia. Here, we found that using optimized shRNAs embedded within an miRNA (shRNAmiR) architecture to achieve ubiquitous knockdown of BCL11A profoundly impaired long-term engraftment of both human and mouse hematopoietic stem cells (HSCs) despite a reduction in nonspecific cellular toxicities...
October 3, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27591578/modulation-of-fetal-hemoglobin-in-hereditary-persistence-of-fetal-hemoglobin-deletion-type-2-compared-to-sicilian-%C3%AE-%C3%AE-thalassemia-by-bcl11a-and-sox6-targeting-micrornas
#20
Thais A Fornari, Carolina Lanaro, Dulcinéia M Albuquerque, Regiane Ferreira, Fernando F Costa
Hereditary persistence of fetal hemoglobin deletion type-2 (HPFH-2) and Sicilian-δβ-thalassemia are conditions described as large deletions of the human β-like globin cluster, with absent β-globin chains and a compensatory variable increase in γ-globin. HPFH, in general, may be distinguished from DB-Thalassemia by higher fetal hemoglobin (HbF) levels, absence of anemia and hypochromic and microcytic erythrocytes. MicroRNAs (miRNAs) regulate a range of cellular processes including erythropoiesis and regulation of transcription factors such as the BCL11A and SOX6 genes, which are related to the regulation of γ-globin expression...
September 3, 2016: Experimental Biology and Medicine
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