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MiRNA in Sickle Cell

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
John G Allen, Mirna Mujacic, Michael J Frohn, Alex J Pickrell, Paul Kodama, Dhanashri Bagal, Tisha San Miguel, E Allen Sickmier, Steve Osgood, Aleksander Swietlow, Vivian Li, John B Jordan, Ki-Won Kim, Anne-Marie C Rousseau, Yong-Jae Kim, Seb Caille, Mike Achmatowicz, Oliver Thiel, Christopher H Fotsch, Pranhitha Reddy, John D McCarter
The efficacy of therapeutic antibodies that induce antibody-dependent cellular cytotoxicity can be improved by reduced fucosylation. Consequently, fucosylation is a critical product attribute of monoclonal antibodies produced as protein therapeutics. Small molecule fucosylation inhibitors have also shown promise as potential therapeutics in animal models of tumors, arthritis, and sickle cell disease. Potent small molecule metabolic inhibitors of cellular protein fucosylation, 6,6,6-trifluorofucose per-O-acetate and 6,6,6-trifluorofucose (fucostatin I), were identified that reduces the fucosylation of recombinantly expressed antibodies in cell culture in a concentration-dependent fashion enabling the controlled modulation of protein fucosylation levels...
October 21, 2016: ACS Chemical Biology
Gift Dineo Pule, Shaheen Mowla, Nicolas Novitzky, Ambroise Wonkam
BACKGROUND: The major therapeutic benefit of hydroxyurea, the only FDA-approved pharmacologic treatment for sickle cell disease (SCD), is directly related to fetal hemoglobin (HbF) production that leads to significant reduction of morbidity and mortality. However, potential adverse effects such as infertility, susceptibility to infections, or teratogenic effect have been subject of concerns. Therefore, understanding HU molecular mechanisms of action, could lead to alternative therapeutic agents to increase HbF with less toxicity...
March 2016: Clinical and Translational Medicine
Constantina Chalikiopoulou, Anastasia-Gerasimoula Tavianatou, Argyro Sgourou, Alexandra Kourakli, Dimitra Kelepouri, Maria Chrysanthakopoulou, Vasiliki-Kaliopi Kanelaki, Evangelos Mourdoukoutas, Stavroula Siamoglou, Anne John, Argyris Symeonidis, Bassam R Ali, Theodora Katsila, Adamantia Papachatzopoulou, George P Patrinos
AIM: Hemoglobinopathies exhibit a remarkable phenotypic diversity that restricts any safe association between molecular pathology and clinical outcomes. PATIENTS & METHODS: Herein, we explored the role of genes involved in the nitric oxide biosynthesis and signaling pathway, implicated in the increase of fetal hemoglobin levels and response to hydroxyurea treatment, in 119 Hellenic patients with β-type hemoglobinopathies. RESULTS: We show that two ASS1 genomic variants (namely, rs10901080 and rs10793902) can serve as pharmacogenomic biomarkers to predict hydroxyurea treatment efficacy in sickle cell disease/β-thalassemia compound heterozygous patients...
March 2016: Pharmacogenomics
Caryn S Gonsalves, Chen Li, Punam Malik, Stanley M Tahara, Vijay K Kalra
Endothelin-1 (ET-1) and plasminogen activator inhibitor-1 (PAI-1) play important roles in pulmonary hypertension (PH) in sickle cell disease (SCD). Our previous studies show higher levels of placenta growth factor (PlGF) in SCD correlate with increased plasma levels of ET-1, PAI-1, and other physiological markers of PH. PlGF-mediated ET-1 and PAI-1 expression occurs via activation of hypoxia-inducible factor-1α (HIF-1α). However, relatively little is understood regarding post-transcriptional regulation of PlGF-mediated expression of ET-1 and PAI-1...
October 12, 2015: Bioscience Reports
Gift D Pule, Shaheen Mowla, Nicolas Novitzky, Charles S Wiysonge, Ambroise Wonkam
AIM: To report on molecular mechanisms of fetal hemoglobin (HbF) induction by hydroxyurea (HU) for the treatment of sickle cell disease. STUDY DESIGN: Systematic review. RESULTS: Studies have provided consistent associations between genomic variations in HbF-promoting loci and variable HbF level in response to HU. Numerous signal transduction pathways have been implicated, through the identification of key genomic variants in BCL11A, HBS1L-MYB, SAR1 or XmnI polymorphism that predispose the response to the treatment, and signal transduction pathways that modulate γ-globin expression (cAMP/cGMP; Giα/c-Jun N-terminal kinase/Jun; methylation and miRNA)...
October 2015: Expert Review of Hematology
Dario Costa, Maria Capuano, Linda Sommese, Claudio Napoli
Hemoglobinopathies are inherited disorders characterized by anomalies of structure, function or production of globin chains. From conception to adulthood, the different expressions over time of the various globin chains depend on the activation/deactivation of different globin genes through methylation and chromatin remodeling processes. The most significant clinical disorders are β-thalassemia and sickle cell disease. The clinical management of these disorders engages regular blood transfusions. Another therapy is represented by allogeneic hematopoietic cells transplantation...
August 2015: Blood Cells, Molecules & Diseases
Anat Aharon, Annie Rebibo-Sabbah, Inna Tzoran, Carina Levin
Extracellular vesicles (EVs), comprised of exosomes, microparticles, apoptotic bodies, and other microvesicles, are shed from a variety of cells upon cell activation or apoptosis. EVs promote clot formation, mediate pro-inflammatory processes, transfer proteins and miRNA to cells, and induce cell signaling that regulates cell differentiation, proliferation, migration, invasion, and apoptosis. This paper will review the contribution of EVs in hematological disorders, including hemoglobinopathies (sickle cell disease, thalassemia), paroxysmal nocturnal hemoglobinuria, and hematological malignancies (lymphomas, myelomas, and acute and chronic leukemias)...
October 2014: Rambam Maimonides Medical Journal
Jaira F de Vasconcellos, Ross M Fasano, Y Terry Lee, Megha Kaushal, Colleen Byrnes, Emily R Meier, Molly Anderson, Antoinette Rabel, Raul Braylan, David F Stroncek, Jeffery L Miller
Induction of fetal hemoglobin (HbF) has therapeutic importance for patients with sickle cell disease (SCD) and the beta-thalassemias. It was recently reported that increased expression of LIN28 proteins or decreased expression of its target let-7 miRNAs enhances HbF levels in cultured primary human erythroblasts from adult healthy donors. Here LIN28A effects were studied further using erythrocytes cultured from peripheral blood progenitor cells of pediatric subjects with SCD. Transgenic expression of LIN28A was accomplished by lentiviral transduction in CD34(+) sickle cells cultivated ex vivo in serum-free medium...
2014: PloS One
Flávia Cristine Mascia Lopes, Regiane Ferreira, Dulcinéia Martins Albuquerque, Angélica A Antoniellis Silveira, Raquel Costa, Raquel Soares, Fernando Ferreira Costa, Nicola Conran
Hydroxyurea (HU), or hydroxycarbamide, is used for the treatment of some myeloproliferative and neoplastic diseases, and is currently the only drug approved by the FDA for use in sickle cell disease (SCD). Despite the relative success of HU therapy for SCD, a genetic disorder of the hemoglobin β chain that results in red-cell sickling, hemolysis, vascular inflammation and recurrent vasoocclusion, the exact mechanisms by which HU actuates remain unclear. We hypothesized that HU may modulate endothelial angiogenic processes, with important consequences for vascular inflammation...
July 2014: Microvascular Research
Sadegh Alijani, Shaban Alizadeh, Ahmad Kazemi, Zahra Kashani Khatib, Masoud Soleimani, Mohamadreza Rezvani, Neda Minayi, Farshid Karami, Behnoosh Tayebi
BACKGROUND: The major hemoglobin in the fetus is hemoglobin F (HbF) (α2γ2), whereas in adult humans, hemoglobin A (α2β2) is predominately expressed. Several studies have indicated that expression of the HbF subunit γ-globin might be regulated post-transcriptionally. This could be done by small non-coding RNAs called microRNAs which target mRNAs in a sequence-specific manner and lead to translational repression or mRNA decay. The aim of this study is to evaluate the effect of miR-26b up-regulation on γ-globin gene expression in K-562 cell line...
January 2014: Avicenna Journal of Medical Biotechnology
Sara Rojas-Jiménez, Johan Lopera-Valle, Mirna Yabur-Espítia
Sickle cell anemia, considered the most prevalent genetic disease among African Americans, is a disease with autosomal recessive inheritance pattern, characterized by the production of hemoglobin S. This abnormal protein polymerizes and facilitates the formation of fibrillar aggregates that alters the erythrocyte morphology. The stiffness of the red blood cells hinders the adequate transit across microcirculation, leading to hemolysis and increased blood viscosity, which ease thrombogenesis and vascular occlusion, resulting in tissue ischemia and microinfarcts...
October 2013: Archivos de Cardiología de México
Fatemeh Kouhkan, Masoud Soleimani, Morteza Daliri, Mehrdad Behmanesh, Naser Mobarra, Majid Mossahebi Mohammadi, Shahin Mohammad, Mehdi Mokhtari, Reyhaneh Lahmy
OBJECTIVE(S): Erythropoiesis is regulated by some extrinsic and intrinsic factors as microRNAs (miRNAs). miRNAs are endogenously small non-coding regulatory RNAs which play vital roles in the variety of cellular fate, critical processes; growth, apoptosis, metabolism, survival of the cells and specially differentiation. Several miRNAs such as miR-16 and miR-451 have been shown to be correlated with erythroid differentiation. Taking into account the importance of miRNAs in cellular differentiation, the goal of the present study was to examine the role of miRNAs in hematopoietic stem cells (HSC) differentiation into the erythroid cells in the absence of growth factors and stimulatory cytokines...
June 2013: Iranian Journal of Basic Medical Sciences
Shilpa Jain, Maria G Kapetanaki, Nalini Raghavachari, Kimberly Woodhouse, Guoying Yu, Suchitra Barge, Claudia Coronnello, Panayiotis V Benos, Gregory J Kato, Naftali Kaminski, Mark T Gladwin
BACKGROUND: Increased platelet activation in sickle cell disease (SCD) contributes to a state of hypercoagulability and confers a risk of thromboembolic complications. The role for post-transcriptional regulation of the platelet transcriptome by microRNAs (miRNAs) in SCD has not been previously explored. This is the first study to determine whether platelets from SCD exhibit an altered miRNA expression profile. METHODS AND FINDINGS: We analyzed the expression of miRNAs isolated from platelets from a primary cohort (SCD = 19, controls = 10) and a validation cohort (SCD = 7, controls = 7) by hybridizing to the Agilent miRNA microarrays...
2013: PloS One
Gregory LaMonte, Nisha Philip, Joseph Reardon, Joshua R Lacsina, William Majoros, Lesley Chapman, Courtney D Thornburg, Marilyn J Telen, Uwe Ohler, Christopher V Nicchitta, Timothy Haystead, Jen-Tsan Chi
Erythrocytes carrying a variant hemoglobin allele (HbS), which causes sickle cell disease and resists infection by the malaria parasite Plasmodium falciparum. The molecular basis of this resistance, which has long been recognized as multifactorial, remains incompletely understood. Here we show that the dysregulated microRNA (miRNA) composition, of either heterozygous HbAS or homozygous HbSS erythrocytes, contributes to resistance against P. falciparum. During the intraerythrocytic life cycle of P. falciparum, a subset of erythrocyte miRNAs translocate into the parasite...
August 16, 2012: Cell Host & Microbe
Ankit A Desai, Tong Zhou, Homaa Ahmad, Wei Zhang, Wenbo Mu, Sharon Trevino, Michael S Wade, Nalini Raghavachari, Gregory J Kato, Marlene H Peters-Lawrence, Tejas Thiruvoipati, Kristin Turner, Nicole Artz, Yong Huang, Amit R Patel, Jason X-J Yuan, Victor R Gordeuk, Roberto M Lang, Joe G N Garcia, Roberto F Machado
RATIONALE: An increased tricuspid regurgitation jet velocity (TRV > 2.5 m/s) and pulmonary hypertension defined by right heart catheterization both independently confer increased mortality in sickle cell disease (SCD). OBJECTIVES: We explored the usefulness of peripheral blood mononuclear cell-derived gene signatures as biomarkers for an elevated TRV in SCD. METHODS: Twenty-seven patients with SCD underwent echocardiography and peripheral blood mononuclear cell isolation for expression profiling and 112 patients with SCD were genotyped for single-nucleotide polymorphisms...
August 15, 2012: American Journal of Respiratory and Critical Care Medicine
Tai-You Ha
MicroRNAs (miRNAs) are a class of naturally occurring small non-coding RNAs of about 22 nucleotides that have recently emerged as important regulators of gene expression at the posttranscriptional level. Recent studies provided clear evidence that microRNAs are abundant in the lung, liver and kidney and modulate a diverse spectrum of their functions. Moreover, a large number of studies have reported links between alterations of miRNA homeostasis and pathological conditions such as infectious diseases, sickle cell disease and endometrium diseases as well as lung, liver and kidney diseases...
December 2011: Immune Network
Vijay G Sankaran
Increased levels of fetal hemoglobin (HbF) can ameliorate the severity of the β-hemoglobin disorders, sickle cell disease (SCD) and β-thalassemia, which are major sources of morbidity and mortality worldwide. As a result, there has been a longstanding interest in developing therapeutic approaches for inducing HbF. For more than 3 decades, the majority of HbF inducers developed were based on empiric observations and have had limited success. Recently, human genetic approaches have provided insight into previously unappreciated regulators of the fetal-to-adult hemoglobin switch and HbF silencing, revealing molecular targets to induce HbF...
2011: Hematology—the Education Program of the American Society of Hematology
Aisha L Walker, Shirley Steward, Thad A Howard, Nicole Mortier, Matthew Smeltzer, Yong-Dong Wang, Russell E Ware
Hydroxyurea has been shown to be efficacious for the treatment of sickle cell anemia (SCA), primarily through the induction of fetal hemoglobin (HbF). However, the exact mechanisms by which hydroxyurea can induce HbF remain incompletely defined, although direct transcriptional effects and altered cell cycle kinetics have been proposed. In this study, we investigated potential epigenetic and alternative molecular mechanisms of hydroxyurea-mediated HbF induction by examining methylation patterns within the (G)γ-globin promoter and miRNA expression within primary CD71(+) erythrocytes of patients with SCA, both at baseline before beginning hydroxyurea therapy and after reaching maximum tolerated dose (MTD)...
November 17, 2011: Blood
Nitin Patel, Stanley M Tahara, Punam Malik, Vijay K Kalra
PAI-1 (plasminogen activator inhibitor-1) is a key physiological inhibitor of fibrinolysis. Previously, we have reported PlGF (placental growth factor)-mediated transcriptional up-regulation of PAI-1 (SERPINE1) mRNA expression via activation of HIF-1α (hypoxia-inducible factor-1α) and AP-1 (activator protein-1) in HPMVECs (human pulmonary microvascular endothelial cells), which resulted in elevated PAI-1 in humans with SCA (sickle cell anaemia). In the present study, we have identified the role of post-transcriptional mechanism(s) of PlGF-mediated accumulation of PAI-1 mRNA in HPMVECs by examining the role of microRNAs (miRNAs/miRs) in PlGF-induced PAI-1 mRNA stability...
March 15, 2011: Biochemical Journal
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