Deletion of the α-globin gene cluster as a cause of acquired α-thalassemia in myelodysplastic syndrome

Blood ◽  
2004 ◽  
Vol 103 (4) ◽  
pp. 1518-1520 ◽  
Author(s):  
David P. Steensma ◽  
Vip Viprakasit ◽  
Alex Hendrick ◽  
David K. Goff ◽  
Joanne Leach ◽  
...  
Keyword(s):  
Blood Cell ◽  
Myelodysplastic Syndrome ◽  
Red Blood Cell ◽  
Globin Gene ◽  
Molecular Defect ◽  
Telomeric Region ◽  
Globin Genes ◽  
Chain Imbalance ◽  
A Minor ◽  
Cell Changes

Abstract Rarely, myelodysplastic syndrome (MDS) is complicated by an acquired form of α-thalassemia (α-thalassemia in myelodysplastic syndrome [ATMDS]) characterized by hypochromic, microcytic, anisopoikilocytic red blood cells with hemoglobin H (HbH) inclusions. Acquired mutations in ATRX, a chromatin remodeling gene, have recently been found in 12 patients with typical features of ATMDS, though they have not been detected in MDS patients with similar red blood cell findings but little HbH. The α-globin genes themselves have appeared normal in all ATMDS patients studied to date. Here we characterize the molecular defect in a unique MDS patient with rare HbH inclusions in which an abnormal clone lost a greater than 1.9-Mb segment of the telomeric region of the short arm of one allele of chromosome 16, including both α-globin genes. Red blood cell changes associated with this acquired somatic genotype (––/αα) are surprisingly severe, demonstrating that a minor globin chain imbalance may be unexpectedly deleterious during the abnormal erythropoiesis that occurs in the context of MDS.

Fetal expression of a human Aγ globin transgene rescues globin chain imbalance but not hemolysis in EKLF null mouse embryos

Blood ◽  
2000 ◽  
Vol 95 (5) ◽  
pp. 1827-1833 ◽  
Author(s):  
A. C. Perkins ◽  
K. R. Peterson ◽  
G. Stamatoyannopoulos ◽  
H. E. Witkowska ◽  
S. H. Orkin
Keyword(s):  
Gene Expression ◽  
Blood Cell ◽  
Red Blood Cell ◽  
Globin Gene ◽  
Cell Physiology ◽  
Null Mouse ◽  
Efficient Production ◽  
Globin Chain ◽  
Chain Imbalance ◽  
Globin Gene Expression

Mice lacking the erythroid Kruppel-like factor (EKLF) die in utero at embryonic day 15 (E15) from severe anemia. EKLF−/− embryos display a marked deficit in β-globin gene expression. To test whether β-globin deficiency was solely responsible for the anemia and intrauterine death, we corrected the globin chain imbalance in EKLF−/− embryos by breeding with a strain of mice that express high levels of human γ-globin. Despite efficient production of hybrid m2-hγ2 hemoglobin in the fetal livers of EKLF−/− animals, hemolysis was not corrected and survival was not prolonged. We concluded that deficiency of nonglobin EKLF target genes is a major contributor to the definitive red blood cell abnormalities and prenatal death in EKLF−/−embryos. These results suggest that strategies designed to antagonize EKLF function in adults with hemoglobinopathy, in an attempt to reactivate γ-globin gene expression, may adversely affect other essential aspects of red blood cell physiology.

scholarly journals Myelodysplastic syndrome: the other cause of anemia in end-stage renal disease patients undergoing dialysis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Min-Yu Chang ◽  
Sheng-Fung Lin ◽  
Shih-Chi Wu ◽  
Wen-Chi Yang
Keyword(s):  
Blood Cell ◽  
Renal Disease ◽  
Myelodysplastic Syndrome ◽  
Red Blood Cell ◽  
End Stage Renal Disease ◽  
Refractory Anemia ◽  
Research Database ◽  
Stage Renal Disease ◽  
End Stage ◽  
Esrd Patients

Abstract In end-stage renal disease (ESRD) patients receiving dialysis, anemia is common and related to a higher mortality rate. Erythropoietin (EPO) resistance and iron refractory anemia require red blood cell transfusions. Myelodysplastic syndrome (MDS) is a disease with hematopoietic dysplasia. There are limited reports regarding ESRD patients with MDS. We aim to assess whether, for ESRD patients, undergoing dialysis is a predictive factor of MDS by analyzing data from the Taiwan National Health Insurance Research Database. We enrolled 74,712 patients with chronic renal failure (ESRD) who underwent dialysis and matched 74,712 control patients. In our study, we noticed that compared with the non-ESRD controls, in ESRD patients, undergoing dialysis (subdistribution hazard ratio [sHR] = 1.60, 1.16–2.19) and age (sHR = 1.03, 1.02–1.04) had positive predictive value for MDS occurrence. Moreover, more units of red blood cell transfusion (higher than 4 units per month) was also associated with a higher incidence of MDS. The MDS cumulative incidence increased with the duration of dialysis in ESRD patients. These effects may be related to exposure to certain cytokines, including interleukin-1, tumor necrosis factor-α, and tumor growth factor-β. In conclusion, we report the novel finding that ESRD patients undergoing dialysis have an increased risk of MDS.

scholarly journals Pathophysiology of β Thalassemia—A Guide to Molecular Therapies

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 31-37 ◽  
Author(s):  
Swee Lay Thein
Keyword(s):  
Globin Gene ◽  
Pathophysiological Mechanism ◽  
Globin Genes ◽  
Membrane Structures ◽  
Pharmacological Agents ◽  
Globin Chains ◽  
Molecular Therapies ◽  
Chain Imbalance ◽  
Chain Synthesis ◽  
Molecular Therapeutic

Abstract The central mechanism underlying the pathophysiology of the β thalassemias can be related to the deleterious effects of imbalanced globin chain synthesis on erythroid maturation and survival. An imbalance of the α/non-α globin chains leads to an excess of unmatched α globin which precipitates out, damaging membrane structures leading to accelerated apoptosis and premature destruction of the erythroid precursors in the bone marrow (ineffective erythropoiesis). Close observation of the genotype/phenotype relationships confirms the pathophysiological mechanism and provides clues to molecular therapies, all of which aim to reduce the α/non-α chain imbalance. They include inheritance of the milder forms of β thalassemia, co-inheritance of α thalassemia, or genetic factors (quantitative trait loci, QTLs) for increasing γ globin expression. Currently, the most promising molecular therapeutic approaches include increasing β globin gene expression by stem cell gene therapy and increasing γ globin expression using pharmacological agents or by transduction of the γ globin genes.

Therapy of Early Stage Myelodysplastic Syndrome (MDS) with Anti-Thymocyte Globulin (ATG) and Etanercept.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1462-1462
Author(s):  
Bart L. Scott ◽  
Aaron L. Holsinger ◽  
Aaravind Ramakrishnan ◽  
Barry Storer ◽  
Pamela S. Becker ◽  
...  
Keyword(s):  
Blood Cell ◽  
Myelodysplastic Syndrome ◽  
Red Blood Cell ◽  
Early Stage ◽  
Pilot Trial ◽  
Risk Groups ◽  
Red Blood Cell Transfusion ◽  
Transfusion Independence ◽  
Phase 2 Trial ◽  
Soluble Tnf Receptor

Abstract Immunosuppressive therapies have proven valuable in treating ineffective hematopoiesis in patients with Myelodysplastic Syndrome (MDS). Following an encouraging pilot trial, we evaluated the combination of equine anti-thymocyte globulin (ATGAM) and the soluble TNF receptor etanercept in a phase 2 trial. So far 23 patients with MDS (6-RA, 4-RARS, 12-RCMD, 1-RAEB-1) in IPSS risk groups low (n=8) or intermediate-1 (n=15) have been enrolled. All patients were platelet or red blood cell transfusion dependent. Nineteen patients completed therapy with I.V. ATGAM at 40mg/kg/day for four consecutive days, followed by etanercept, 25mg s.c. twice a week for 2 weeks every month for 4 months. The regimen was well tolerated and the majority of adverse events were anticipated infusional reactions related to ATGAM administration. Responses were assessed by modified International Working Group criteria. Twelve patients had hematological improvement (HI)-erythroid, 2 HI-neutrophil, and 3 HI-platelet. Five patients achieved red blood cell and one patient platelet transfusion independence. There was one complete remission in a patient with a co-existing diagnosis of multiple sclerosis. Thus, the overall response rate by intent to treat analysis among the 23 patients was 61%. Four patients did not complete their first course of therapy due to anaphylactic reaction, thrombosis of a pre-existing femoral graft, myocardial infarction, and patient preference. Among patients who completed treatment 74% had a hematological response, with duration of at least 5 months. Combination therapy with ATG and etanercept was active and safe in unselected patients with low and intermediate-1 risk MDS.

Diagnosis and Management of Anemia in Patients with the Myelodysplastic Syndrome

1998 ◽  
Vol 5 (2_suppl) ◽  
pp. 41-45 ◽  
Author(s):  
John M. Bennett ◽  
Peter A. Kouides
Keyword(s):  
Bone Marrow ◽  
Blood Cell ◽  
Myelodysplastic Syndrome ◽  
Red Blood Cell ◽  
Red Blood Cell Transfusion ◽  
Recombinant Erythropoietin ◽  
Bone Marrow Blast ◽  
Diagnosis And Management ◽  
Specific Factors

While not appropriate for all patients with the myelodysplastic syndrome, recombinant erythropoietin (EPO) is a possible alternative to red blood cell transfusion. Specific factors such as the presence of cytopenias, the bone marrow blast percentage, and cytogenetic findings determine which patients are good candidates for treatment with EPO.

scholarly journals Red blood cell changes during the evolution of the sickle cell painful crisis

Blood ◽  
1992 ◽  
Vol 79 (8) ◽  
pp. 2154-2163 ◽  
Author(s):  
SK Ballas ◽  
ED Smith
Keyword(s):  
Blood Cell ◽  
Sickle Cell ◽  
Red Blood Cell ◽  
Reticulocyte Count ◽  
Hemoglobin Level ◽  
Second Phase ◽  
Osmotic Gradient ◽  
Cell Changes ◽  
Painful Crisis ◽  
Rbc Deformability

Abstract A longitudinal study of the red blood cell (RBC) deformability, percent of dense erythrocytes, and hematologic parameters has been conducted during 117 painful crises affecting 36 patients with sickle cell anemia between January, 1985 and December, 1990. RBC deformability was determined by osmotic gradient ektacytometry and the percentage of dense cells was quantitated by centrifugation on a discontinuous Stractan density gradient. The data indicate that the painful crisis is a process that follows a bimodal form of evolution. The first phase of the painful crisis is characterized by increase in the severity of pain, increase in the number of dense cells, and a decrease in RBC deformability. In some patients the changes in dense cells and RBC deformability are evident 1 to 3 days before the onset of pain. In addition, the hemoglobin level decreases and the reticulocyte count increases during this initial phase. The second phase of the crisis is characterized by reduction in pain intensity, decrease in the number of dense cells, and increase in RBC deformability to values higher than those seen in the steady state. Moreover, the improvement in RBC deformability and the decrease in the number of dense cells at the end of a crisis seem to constitute new risk factors that may incite a recurrence of the crisis within 1 month in about 50% of painful episodes. The pathophysiologic events responsible for this bimodal behavior of RBCs during painful episodes may represent the appearance of factors that induce (1) preferential trapping of deformable cells in the microcirculation during the first phase of the crisis, followed by a decrease of dense cells and the appearance of new deformable RBCs released from the bone marrow during the second phase of the crisis; or (2) variable sickling of all circulating RBCs during the first phase followed by disappearance of dense RBCs and their replenishment by deformable cells during the second phase.

Homozygous Expression of a Novel Senegalese-Type Partial Deletion of the Beta and Delta Genes Causes a Delta0 Beta+ Thalassemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2128-2128
Author(s):  
Hernan Sabio ◽  
Natalia Dixon ◽  
Ferdane Kutlar ◽  
Niren Patel ◽  
Hanfang Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Analysis ◽  
Conflicts Of Interest ◽  
Clinical Phenotype ◽  
Globin Gene ◽  
African Ancestry ◽  
Beta Thalassemia ◽  
Globin Genes ◽  
Chain Imbalance ◽  
Globin Gene Expression

Abstract Abstract 2128 Clinical phenotype in β-thalassemia syndromes is determined by the degree of chain imbalance. An increase in γ-globin production will compensate for the absent or deficient β-globin synthesis and will result in the amelioration of the chain imbalance, and hence an improvement in clinical features. The known genotypes of δβ-thalassemia are associated with an increase in Hb F production, which results in the amelioration of the clinical presentation. Most δβ-thalassemias result from deletions that remove the δ- and β-globin genes, (δβ)0 with a compensatory increase in γ-globin (Hb F) expression. We report an unusual case of homozygous δ0β+ thalassemia that provides interesting insights into increased γ-globin expression and the regulation of β-globin gene expression. An 8-year old boy of African ancestry presented with lifelong jaundice and pallor. He also experienced episodes of worsening symptoms. He exhibited frontal bossing, pale mucosa, scleral icterus, and moderate splenomegaly. He was known to have G6PD deficiency and was suspected of having additional erythrocyte pathology. The CBC revealed a Hb of 8.7, Hct 26.4, MCV 64.7, WBC 10,700, platelets 283,000, reticulocytes 2.2%, and total bilirubin 5.3. Hemoglobin analysis by HPLC and IEF revealed HbA 13.4%, Hb F 86.6%, and no additional components. Alpha thalassemia −3.7kb deletion was not detected. Globin chain analysis revealed α, β, Gγ and AγI chains. DNA analysis revealed a novel Senegalese-type deletion of the beta and delta genes, resulting in a delta0 beta+ thalassemia. The subject's parents who were both from the same small village in Niger had normal hematology values. Their hemoglobin analyses revealed Hb A 94. 8%, Hb A2 2.0%, Hb F 3.2% and Hb A 93.5%, Hb A2 2.1%, Hb F 4.5% in the father and mother, respectively. They were both heterozygous for the delta-beta deletion identified in their son. DNA analysis revealed a breakpoint in the delta gene at nucleotides 54755–54760 and a breakpoint in the beta gene at nucleotides 62153– 62158 [GenBank Ref ID: HUMHBB] with a 5 nucleotide “CAACA” bp region overlapping area. The subject, who is homozygous for the identified deletions, has a clinical phenotype of thalassemia intermedia. He has not yet required red cell transfusions. This is the first instance of a Senegalese-type deletion occurring in the homozygous state. The genotype provides insights into regulation of globin gene expression. While the ∼7 Kb deletion in the δβ-intergenic region may be responsible for the increased expression of the γ-globin gene similar to Hb Lepore deletions, the continued low level expression of the β-globin gene is most probably the result of the juxtaposition of the inefficient δ-globin promoter brought in the vicinity of the β-globin gene. Disclosures: No relevant conflicts of interest to declare.

Clinical and Biological Characterization of Patients with Low/Intermediate-1 Risk Myelodysplastic Syndrome and Iron Overload

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4956-4956
Author(s):  
David Ivars ◽  
Rosa Collado ◽  
Carmen Alguero ◽  
M Carmen Tormos ◽  
Laura Diaz ◽  
...  
Keyword(s):  
Blood Cell ◽  
Oxidative Damage ◽  
Myelodysplastic Syndrome ◽  
Iron Overload ◽  
Red Blood Cell ◽  
Research Funding ◽  
Who Classification ◽  
Hfe Gene ◽  
Endocrine Disorders ◽  
Increased Risk

Abstract Abstract 4956 Introduction. Patients with Myelodysplastic Syndrome (MDS) are susceptible to developing iron overload as a response to the red blood cell (RBC) transfusions and ineffective hematopoiesis. This iron overload (IOL) is characterized by an increase in oxygen-reactive species accompanied by a decrease in antioxidants, and results in hepatic, cardiac and endocrine disorders, as well as an increased risk of infection. Ineffective hematopoiesis promotes iron absorption at intestinal level. This process is enhanced by the presence of mutations in the hereditary hemochromatosis gene (HFE). This study aims to define the features that accompany patients with iron overload, comparing them to a MDS population at diagnosis. Patients and methods. 34 low/int-1 MDS patients (International Prognostic Score System, IPSS) were assessed, 22 of them at diagnosis and 12 patients when IOL was developed. Peripheral blood samples were drawn after informed consent was obtained from the patient or the patient′s guardians in accordance with the Declaration of Helsinki. The analyzed parameters were: WHO classification, sex, age, blood count, number of RBC units received, iron metabolism, and mutations of the HFE gene. Liver damage was estimated by measuring Alanine transaminase (ALT) levels, and liver iron concentration (LIC) detected by Magnetic Resonance (MR). Likewise, levels of labile plasmatic iron (LPI) (eLPI Assay Kit, Aferrix) were quantified by spectrofluorimetric determination. Oxidative damage was assessed by quantifying the modified base 8-oxo-2-hydroxi-deoxiguanosine (8-oxo-dG) by means of High-Performance Liquid Chromatography (HPLC) and the O2− anion levels by flow cytometry. Results. According to the WHO classification, 72. 2% of cases with MDS and IOL assessed belonged to Refractory Sideroblastic Anemia (RSA) group, unlike 27. 3% of patients at diagnosis (p=0. 0265). In comparison to diagnosis patients, IOL subjects presented lower mean age (76 vs. 81 years; p=0. 0172), hemoglobin levels (7. 5 ± 0. 4 vs. 10. 3 ± 0. 3 g/dl; p<0. 0001), and red blood cell count (2. 3 ± 0. 1 vs. 3. 0 ± 0. 1×109/l; p<0. 0001). Moreover, higher levels of ferritin (median 1147 vs. 219 μg/dl; p<0. 0001), Transferrin Saturation Index (TSI) (median 89. 4 vs. 31. 5%; p<0. 0001) and ALT (median 14. 9 vs. 11. 0 U/l; p=0. 0263) were observed when compared to the diagnosis patients. On the other hand, among IOL patients the average levels for LIC were 13. 8 ± 2. 0 mg Fe/g (normal levels <4. 0 mg Fe/g), and higher LPI concentrations were detected (median 1. 2 vs. 0. 1 U; p<0. 0001). These patients received an average of 28 ± 9 RBC units. Interestingly, two of the patients developed IOL without previously having received any transfusions; both of whom were diagnosed with RSA, having the H63D mutation of the HFE gene. Regarding the oxidative damage, in patients with IOL a significant increase of 8-oxo-dG (p=0. 0040) and O2− anions (p=0. 0157) was observed. Conclusions. Disclosures: Carbonell: Novartis Farmacéutica, S. A.: Research Funding; Universitat de València: Research Funding.

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