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Ring sideroblasts

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https://www.readbyqxmd.com/read/28870615/luspatercept-for-the-treatment-of-anaemia-in-patients-with-lower-risk-myelodysplastic-syndromes-pace-mds-a-multicentre-open-label-phase-2-dose-finding-study-with-long-term-extension-study
#1
Uwe Platzbecker, Ulrich Germing, Katharina S Götze, Philipp Kiewe, Karin Mayer, Jörg Chromik, Markus Radsak, Thomas Wolff, Xiaosha Zhang, Abderrahmane Laadem, Matthew L Sherman, Kenneth M Attie, Aristoteles Giagounidis
BACKGROUND: Myelodysplastic syndromes are characterised by ineffective erythropoiesis. Luspatercept (ACE-536) is a novel fusion protein that blocks transforming growth factor beta (TGF β) superfamily inhibitors of erythropoiesis, giving rise to a promising new investigative therapy. We aimed to assess the safety and efficacy of luspatercept in patients with anaemia due to lower-risk myelodysplastic syndromes. METHODS: In this phase 2, multicentre, open-label, dose-finding study (PACE-MDS), with long-term extension, eligible patients were aged 18 years or older, had International Prognostic Scoring System-defined low or intermediate 1 risk myelodysplastic syndromes or non-proliferative chronic myelomonocytic leukaemia (white blood cell count <13 000/μL), and had anaemia with or without red blood cell transfusion support...
September 1, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28731922/a-novel-g-55040074delt-in-alas2-gene-resulting-in-a-monomeric-protein-and-severe-sideroblastic-anemia-phenotype
#2
Prateek Bhatia, Aditya Singh, Avani Hedge
Sideroblastic anemias are a rare group of disorders resulting from defective iron incorporation during heme synthesis and hence characterized by anemia and presence of ringed sideroblasts in bone marrow. The most common form is an X-linked disorder caused by mutations in ALAS2 gene. In the current paper, a case of X-linked sideroblastic anemia caused by a novel homozygous deletional mutation in exon 10 of ALAS2 gene is presented. The female infant developed moderately severe anemia at 6 months of age, which did not improve despite adequate nutritional support...
August 2017: Journal of Pediatric Hematology/oncology
https://www.readbyqxmd.com/read/28667034/a-novel-alas2-mutation-resulting-in-variable-phenotypes-and-pyridoxine-response-in-a-family-with-x-linked-sideroblastic-anemia
#3
Jee-Soo Lee, JaYoon Gu, Hyun Ju Yoo, Youngil Koh, Hyun Kyung Kim
We report a novel ALAS2 gene mutation c.1315A>G (p.Lys439Glu) identified in a family, which caused evidently different hematologic phenotypes. The proband was a 17-year-old man with severe microcytic hypochromic anemia, excessive ring sideroblasts in the bone marrow, and iron overload. A hemizygous ALAS2 mutation in exon 9, c.1315A>G (p.Lys439Glu), was identified through sequence analysis. We assume that this amino acid substitution affects the enzymatic activity of ALAS2 by affecting its interaction with the cofactor pyridoxal 5'-phosphate, since the patient was responsive to pyridoxine treatment...
May 2017: Annals of Clinical and Laboratory Science
https://www.readbyqxmd.com/read/28642303/molecular-analysis-of-myelodysplastic-syndrome-with-isolated-del-5q-reveals-a-specific-spectrum-of-molecular-mutations-with-prognostic-impact-a-study-on-123-patients-and-27-genes
#4
Manja Meggendorfer, Claudia Haferlach, Wolfgang Kern, Torsten Haferlach
The only cytogenetic aberration defining a myelodysplastic syndrome subtype is the deletion of the long arm of chromosome 5, giving with morphological features the diagnosis of myelodysplastic syndrome with isolated del(5q). These patients show a good prognosis and respond to treatment such as lenalidomide, but some cases progress to acute myeloid leukemia. However, the molecular mutation pattern is rarely characterized. Therefore, we investigated a large cohort of 123 myelodysplastic syndrome patients with isolated del(5q) diagnosed following the World Health Organization classifications 2008 and 2016 by sequencing 27 genes...
June 22, 2017: Haematologica
https://www.readbyqxmd.com/read/28634182/sf3b1-initiating-mutations-in-mds-rss-target-lymphomyeloid-hematopoietic-stem-cells
#5
Teresa Mortera-Blanco, Marios Dimitriou, Petter S Woll, Mohsen Karimi, Edda Elvarsdottir, Simona Conte, Magnus Tobiasson, Monika Jansson, Iyadh Douagi, Matahi Moarii, Leonie Saft, Elli Papaemmanuil, Sten Eirik W Jacobsen, Eva Hellström-Lindberg
Mutations in the RNA splicing gene SF3B1 are found in >80% of patients with myelodysplastic syndrome with ring sideroblasts (MDS-RS). We investigated the origin of SF3B1 mutations within the bone marrow hematopoietic stem and progenitor cell compartments in patients with MDS-RS. Screening for recurrently mutated genes in the mononuclear cell fraction revealed mutations in SF3B1 in 39 of 40 cases (97.5%), combined with TET2 and DNMT3A in 11 (28%) and 6 (15%) patients, respectively. All recurrent mutations identified in mononuclear cells could be tracked back to the phenotypically defined hematopoietic stem cell (HSC) compartment in all investigated patients and were also present in downstream myeloid and erythroid progenitor cells...
August 17, 2017: Blood
https://www.readbyqxmd.com/read/28600336/diagnosis-and-classification-of-hematologic-malignancies-on-the-basis-of-genetics
#6
REVIEW
Justin Taylor, Wenbin Xiao, Omar Abdel-Wahab
Genomic analysis has greatly influenced the diagnosis and clinical management of patients affected by diverse forms of hematologic malignancies. Here, we review how genetic alterations define subclasses of patients with acute leukemias, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), non-Hodgkin lymphomas, and classical Hodgkin lymphoma. These include new subtypes of acute myeloid leukemia defined by mutations in RUNX1 or BCR-ABL1 translocations as well as a constellation of somatic structural DNA alterations in acute lymphoblastic leukemia...
July 27, 2017: Blood
https://www.readbyqxmd.com/read/28554891/dna-repair-gene-expressions-are-related-to-bone-marrow-cellularity-in-myelodysplastic-syndrome
#7
Howard L Ribeiro, Allan Rodrigo S Maia, Roberta Taiane G de Oliveira, Marília Braga Costa, Izabelle Rocha Farias, Daniela de Paula Borges, Juliana Cordeiro de Sousa, Silvia Maria M Magalhães, Ronald F Pinheiro
OBJECTIVE: To evaluate the expression of genes related to nuclear excision (ERCC8, XPA and XPC), homologous recombination and non-homologous end-joining (ATM, BRCA1, BRCA2 and LIG4) repair mechanisms, using quantitative PCR methodologies, and it relation with bone marrow cellularity in myelodysplastic syndrome (MDS). METHODS AND RESULTS: A total of 51 adult de novo patients with MDS (3 refractory anaemia (RA), 11 refractory anaemia with ringed sideroblasts (RARS), 28 refractory cytopenia with multilineage dysplasia (RCMD), 3 refractory anaemia with excess blasts type I (RAEB-I), 5 refractory anaemia with excess blasts type II (RAEB-II), and 1 chronic myelomonocytic leukaemia (CMML) were evaluated...
May 29, 2017: Journal of Clinical Pathology
https://www.readbyqxmd.com/read/28545085/splicing-factor-sf3b1k700e-mutant-dysregulates-erythroid-differentiation-via-aberrant-alternative-splicing-of-transcription-factor-tal1
#8
Shuiling Jin, Hairui Su, Ngoc-Tung Tran, Jing Song, Sydney S Lu, Ying Li, Suming Huang, Omar Abdel-Wahab, Yanyan Liu, Xinyang Zhao
More than 60% of myeloid dysplasia syndrome (MDS) contains mutations in genes encoding for splicing factors such as SF3B1, U2AF, SRSF2 and ZRSR2. Mutations in SF3B1 are associated with 80% cases of refractory anemia with ring sideroblast (RARS), a subtype of MDS. SF3B1K700E is the most frequently mutated site among mutations on SF3B1. Yet the molecular mechanisms on how mutations of splicing factors lead to defective erythropoiesis are not clear. SF3B1K700E mutant binds to an RNA binding protein, RBM15, stronger than the wild type SF3B1 protein in co-immunoprecipitation assays...
2017: PloS One
https://www.readbyqxmd.com/read/28484169/current-diagnosis-and-treatment-for-myelodysplastc-syndromes
#9
Tomoko Hata
Genetic analysis of myelodysplastic syndrome (MDS) using next-generation sequencing yields medcially important information, showing gene mutations in 90% of MDS cases. The World Health Organization (WHO) classification was revised in 2016 to incorporate SF3B1 gene mutations, frequently seen in MDS with ringed sideroblasts, into the diagnostic criteria. Unlike the poor prognosis seen in cases with ASXL1, EZH2, RUNX1 and in particular, TP53 MDS-related mutations, SF3B1 gene mutations show a favorable prognosis...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28484165/biology-of-sideroblastic-anemia
#10
Hideo Harigae
Sideroblastic anemia is characterized by anemia with ring sideroblasts produced by the bone marrow. Sideroblasts are formed by disutilization and deposit of iron in the mitochondoria. There are two forms of sideroblastic anemia: congenital and acquired. Congenital sideroblastic anemia is caused by mutations in genes involved in heme biosynthesis, iron-sulfur (Fe-S) cluster biogenesis, or mitochondrial metabolism. Although there is a variation in the mutated genes among races, the most common congenital sideroblastic anemia is X-linked sideroblastic anemia caused by mutations in the erythroid-specific δ-aminolevulinate synthase gene, which is the first enzyme of heme biosynthesis in erythroid cells...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28466384/splicing-factor-mutations-in-mds-rars-and-mds-mpn-rs-t
#11
REVIEW
Akihide Yoshimi, Omar Abdel-Wahab
Spliceosomal mutations, especially mutations in SF3B1, are frequently (>80%) identified in patients with refractory anemia with ringed sideroblasts (RARS) and myelodysplastic/myeloproliferative neoplasms with ringed sideroblasts and thrombocytosis (MDS/MPN-RS-T; previously known as RARS-T), and SF3B1 mutations have a high positive predictive value for disease phenotype with ringed sideroblasts. These observations suggest that SF3B1 mutations play important roles in the pathogenesis of these disorders and formation of ringed sideroblasts...
June 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28401094/refractory-anemia-with-ring-sideroblasts-and-thrombocytosis
#12
Sarita Pradhan
No abstract text is available yet for this article.
March 2017: Blood Research
https://www.readbyqxmd.com/read/28395441/-mutational-analysis-of-rna-splicing-machinery-genes-sf3b1-u2af1-and-srsf2-in-118-patients-with-myelodysplastic-syndromes-and-related-diseases
#13
J Y Wang, J Ma, Y N Lin, J Wang, H Shen, F M Gui, C Han, Q H Li, Z Song, X J Wang
Objective: To investigate the incidence, molecular features and clinical significance of RNA splicing machinery genes mutation in myelodysplastic syndromes (MDS) and related diseases. Methods: Mutational analysis of splicing factor 3B subunit 1 (SF3B1) (K700E) , U2 small nuclear RNA auxiliary factor 1 (U2AF1) (S34, Q157P) and serine/arginine-rich splicing factor 2 (SRSF2) (P95) in 118, de novo MDS and related diseases were separately performed by using polymerase chain reaction (PCR) followed by sequence analysis...
March 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28395431/-nix-mediated-mitochondrial-autophagy-in-pathogenesis-of-myelodysplastic-syndrome-anemia
#14
L Y Yang, N B Cui, H Q Wang, R Fu, W Qu, E B Ruan, X M Wang, G J Wang, Y H Wu, H Liu, J Song, J Guan, L M Xing, L J Li, H J Jiang, H Liu, Y H Wang, C Y Liu, W Zhang, Z H Shao
Objective: To investigate the change of NIX level of bone marrow nucleated red blood cells in anemia patients with myelodysplastic syndromes (MDS), to explore the significance of NIX-mediated mitochondrial autophagy in the pathogenesis of MDS anemia. Methods: A total of 54 patients with MDS diagnosed in the Department of Hematology of General Hospital, Tianjin Medical University from July 2015 to July 2016 were enrolled into the MDS group, 33 cases of immune thrombocytopenia or idiopathic leukopenia as controls...
April 11, 2017: Zhonghua Yi Xue za Zhi [Chinese medical journal]
https://www.readbyqxmd.com/read/28370157/an-exploratory-clinical-trial-of-bortezomib-in-patients-with-lower-risk-myelodysplastic-syndromes
#15
May Daher, Juliana Elisa Hidalgo Lopez, Jasleen K Randhawa, Kausar Jabeen Jabbar, Yue Wei, Naveen Pemmaraju, Gautam Borthakur, Tapan Kadia, Marina Konopleva, Hagop M Kantarjian, Katherine Hearn, Zeev Estrov, Steven Reyes, Carlos E Bueso-Ramos, Guillermo Garcia-Manero
Myelodysplastic syndromes (MDSs) are characterized by ineffective hematopoiesis and an increased risk of transformation. Few effective therapies are available for lower risk MDS patients, especially after the failure of hypomethylating agents. MDS progenitor cells are dependent on the nuclear factor-κB (NF-κB) for survival, which makes it an attractive therapeutic target. As a proteosomal inhibitor, bortezomib is thought to have inhibitory activity against NF-κB. We designed a proof-of-principle study of subcutaneous (SC) bortezomib in lower risk MDS patients with evidence of NF-κB activation in their bone marrow...
July 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28300669/enhanced-plasma-protein-carbonylation-in-patients-with-myelodysplastic-syndromes
#16
Alžběta Hlaváčková, Jana Štikarová, Kristýna Pimková, Leona Chrastinová, Pavel Májek, Roman Kotlín, Jaroslav Čermák, Jiří Suttnar, Jan Evangelista Dyr
Myelodysplastic syndromes (MDS) represent a heterogeneous group of pre-leukemic disorders, characterized by ineffective hematopoiesis and the abnormal blood cell development of one or more lineages. Oxidative stress, as an important factor in the carcinogenesis of onco-hematological diseases, is also one of the known factors involved in the pathogenesis of MDS. An increase of reactive oxygen species (ROS) may lead to the oxidation of DNA, lipids, and proteins, thereby causing cell damage. Protein carbonylation caused by ROS is defined as an irreversible post-translational oxidative modification of amino acid side chains, and could play an important role in signaling processes...
March 12, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28293405/diagnostic-utility-of-flow-cytometry-in-myelodysplastic-syndromes
#17
REVIEW
Matteo G Della Porta, Cristina Picone
The pathological hallmark of myelodysplastic syndromes (MDS) is marrow dysplasia, which represents the basis of the WHO classification of these disorders. This classification provides clinicians with a useful tool for defining the different subtypes of MDS and individual prognosis. The WHO proposal has raised some concern regarding minimal diagnostic criteria particularly in patients with normal karyotype without robust morphological markers of dysplasia (such as ring sideroblasts or excess of blasts). Therefore, there is clearly need to refine the accuracy to detect marrow dysplasia...
2017: Mediterranean Journal of Hematology and Infectious Diseases
https://www.readbyqxmd.com/read/28222336/a-two-step-approach-for-sequencing-spliceosome-related-genes-as-a-complementary-diagnostic-assay-in-mds-patients-with-ringed-sideroblasts
#18
Kamila Janusz, Mónica Del Rey, María Abáigar, Rosa Collado, David Ivars, María Hernández-Sánchez, Alberto Valiente, Cristina Robledo, Rocío Benito, María Díez-Campelo, Fernando Ramos, Alexander Kohlmann, Consuelo Del Cañizo, Jesús María Hernández-Rivas
Our study aimed to analyze the presence of mutations in SF3B1 and other spliceosome-related genes in myelodysplastic syndromes with ringed sideroblasts (MDS-RS) by combining conventional Sanger and next-generation sequencing (NGS) methods, and to determine the feasibility of this approach in a clinical setting. 122 bone marrow samples from MDS-RS patients were studied. Initially, exons 14 and 15 of the SF3B1 gene were analyzed by Sanger sequencing. Secondly, they were studied by NGS covering besides SF3B1, SRSF2, U2AF1 and ZRSR2 genes...
May 2017: Leukemia Research
https://www.readbyqxmd.com/read/28188970/refractory-anemia-with-ring-sideroblasts-rars-and-rars-with-thrombocytosis-rars-t-2017-update-on-diagnosis-risk-stratification-and-management
#19
REVIEW
Mrinal M Patnaik, Ayalew Tefferi
DISEASE OVERVIEW: Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include refractory anemia with ring sideroblasts (RARS), now classified under myelodysplastic syndromes with RS (MDS-RS) and RARS with thrombocytosis (RARS-T); now called myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T). DIAGNOSIS: MDS-RS is a lower risk MDS, with single or multilineage dysplasia (SLD/MLD), <5% bone marrow (BM) blasts and ≥15% BM RS (≥5% in the presence of SF3B1 mutations)...
March 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28167288/impact-of-tet2-deficiency-on-iron-metabolism-in-erythroblasts
#20
Kyoko Inokura, Tohru Fujiwara, Kei Saito, Tatsuya Iino, Shunsuke Hatta, Yoko Okitsu, Noriko Fukuhara, Yasushi Onishi, Kenichi Ishizawa, Kazuya Shimoda, Hideo Harigae
Sideroblastic anemia is characterized by the presence of ring sideroblasts (RSs), which are caused by iron accumulation in the mitochondria of erythroblasts and are present in both the acquired and congenital forms of the disease. However, the mechanism leading to RS formation remains elusive. Acquired sideroblastic anemia is usually observed in myelodysplastic syndrome (MDS). Because a subset of MDS harbors a somatic mutation of TET2, it may be involved in iron metabolism and/or heme biosynthesis in erythroblasts...
May 2017: Experimental Hematology
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