Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019045 (hemoglobinopathies)
 2,704 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High levels of HbF were found in patients with myelodysplastic syndrome (MDS), as well as a possible switching of the ratio of the gamma chains from the adult to the newborn type in 25% of our patients. These abnormalities in general were not present in the parents. The possibility of having thalassemia or other hemoglobinopathies was excluded. The fetal hemoglobin percentage was quantitated by alkali denaturation of the hemolysate, and the gamma chain content was determined in blood hemolysate by HPLC following HbF isolation. A 7/3 ratio of fetal Gy/Ay was found in three patients. Since the survival of MDS patients with high HbF levels was longer than that of patients with low levels of HbF, this finding may be used as a potential prognostic factor.
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PMID:Quantitation of HBF gamma-chain types by HPLC in patients with myelodysplastic syndrome. 172 40

Anatomical observations have indicated a decrease of marrow cellularity with age, but these changes are not associated with anemia in the healthy geriatric patient. Aged patients with refractory anemia should be studied by utilizing red cell volume (MCV) and red cell heterogeneity (RDW). A classification with these indices initially can separate the anemias for a more fruitful investigation. By old age the anemias of hereditary red cell membrane or hemoglobin disorders should be known to the patient. In the absence of tumor, elderly patients have an increasing frequency of refractory anemias that can be called preleukemia or myelodysplastic syndrome. Morphological observations have emphasized the importance of abnormal megakaryocytes and platelets in all phases of preleukemia, and these cytologic changes should be used to guide the physician in the early diagnosis of the syndrome complex. This group of refractory anemias have a limited survival, but nonspecific marrow stimulation can be effective and should be tried. With a more complete classification of the chromosomal abnormalities in the myelodysplastic syndrome, a more accurate prognosis can be anticipated. The anemias of marrow aplasia and ineffective iron utilization (anemia of chronic disease) are found frequently in the elderly, and the physician may offer more effective therapy by an early diagnosis.
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PMID:Refractory anemia in the elderly. 354 48

The rheumatologic manifestations of hemophilia and the hemoglobinopathies have been previously reviewed. Recent observations on the management and complications of these disorders are presented. Although rheumatologic manifestations are well recognized in leukemias and lymphomas, most of the observations have been based on small series of patients and case reports. This review focuses on leukemias and lymphomas, and brief reference is made to the myelodysplastic syndromes.
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PMID:Rheumatologic features of hematologic disorders. 886 41

There is accumulating evidence that the marrow-failure of myelodysplastic syndrome (MDS) is immune-mediated. We studied patients with MDS to look for oligoclonal or clonal expansion in T cells indicative of an autoimmune process. We used a PCR-based technique (spectratyping) to characterize the T cell repertoire in MDS (n=15; 9 RA, 4 RARS, 2 RAEB) and compared results with age-matched healthy donors (n=20) and transfusion-dependent (TD) patients with hemoglobinopathy (n=5). We found a significantly higher number of skewed Vbeta profiles in the MDS patients compared with controls. In peripheral blood T cells, 60/345 Vbeta profiles examined were skewed in MDS patients compared with 3/115 Vbeta profiles in TD controls (P<0.0001), and 58/460 Vbeta profiles in age-matched controls (P=0.05). A study of Jbeta region within the skewed Vbeta profiles revealed preferential usage of Jbeta 2.1 in MDS in contrast with a wide distribution over the entire Jbeta spectrum in controls, consistent with non-random T cell clonal expansion in MDS. These findings provide further evidence that T cell mediated immune processes are a feature of MDS.
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PMID:Oligoclonal T cell expansion in myelodysplastic syndrome: evidence for an autoimmune process. 1168 79

Although most of the diagnostic applications of flow cytometry bring forth examples of leukocyte immunophenotyping for immunodeficiency diseases and leukemia-lymphoma diagnosis, the same technology has improved medical assessment of diseases affecting the red cell and erythropoiesis. Flow cytometric methods were first applied to laboratory hematology with the improvement in reticulocyte counting and the creation of the immature reticulocyte fraction for better anemia evaluation and therapeutic monitoring. A more recent improvement attributable to flow cytometry is accurate detection of fetal red cells in the evaluation of FMH hemorrhage. The same method used in the detection of fetal RBCs based on HbF content measurement using monoclonal antibodies also offers the potential for enumeration of F cells, which promises to have use in therapeutic monitoring of patients with sickle cell disease and the evaluation of other hemoglobinopathies and myelodysplasia. Other clinical uses of flow cytometric RBC analysis include nonisotopic red cell survival studies, sensitive blood group typing, sensitive detection of immune-mediated hemolytic diseases, and evaluation of parasitic diseases whose life cycle involves intracellular RBC infestation. This article summarizes red cell flow cytometry, particularly as it impacts the areas of immunohematology and laboratory hematology, and points to areas of potential future contribution of this technology to diagnostic medicine.
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PMID:Diagnostic utility of red cell flow cytometric analysis. 1177 Feb 90

Abnormalities of hemoglobin synthesis are usually inherited but may also arise as a secondary manifestation of another disease, most commonly hematologic neoplasia. Acquired hemoglobin disorders can be seen in any population and are not restricted to areas of the world with high incidences of inherited hemoglobinopathies. In fact, the acquired hemoglobinopathies may be more readily recognized where inherited hemoglobin abnormalities are rare and less likely to cause diagnostic confusion. Acquired alpha-thalassemia is the best characterized of the acquired red blood cell disorders in patients with hematologic malignancy, and it is almost always associated with a myelodysplastic syndrome (MDS). At least 2 molecular mechanisms for acquired alpha-thalassemia are now recognized: acquired deletion of the alpha-globin gene cluster limited to the neoplastic clone and, more commonly, inactivating somatic mutations of the trans-acting chromatin-associated factor ATRX, which cause dramatic down-regulation of alpha-globin gene expression. Here we review the clinical, hematologic, and molecular genetic features of alpha-thalassemia arising in a clonal myeloid disorder, and we discuss howATRX might affect gene expression in normal and abnormal hematopoiesis through epigenetic mechanisms.
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PMID:Acquired alpha-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies. 1535 26

DNA methylation provides a major epigenetic code (besides histone modification) of the lineage- and development-specific genes (such as regulators of differentiation in the hematopoietic lineages) that control expression of normal cells. However, DNA methylation is also involved in malignancies because aberrant methylating gene activity occurs during leukemic transformation. Thus, genes such as tumor suppressor genes, growth-regulatory genes, and adhesion molecules are often silenced in various hematopoietic malignancies by epigenetic inactivation via DNA hypermethylation. This inactivation is frequently seen not only in transformed cell lines but also in primary leukemia cells. Because this defect is amenable to reversion by pharmacologic means, agents that inhibit DNA methylation have been developed to specifically target this hypermethylation defect in leukemia and preleukemia cases. The most clinically advanced agents, the azanucleosides 5-azacytidine and 5-aza-2'-deoxycytidine (decitabine), were discovered more than 25 years ago, when their methylation-inhibitory activities, even at low concentrations, became apparent. Although both of these agents, like cytarabine, had been clinically used until then at high doses, the redevelopment of these agents for low-dose schedules has revealed very interesting clinical activities for treating myelodysplasia (MDS) and acute myeloid leukemia (AML). Because these diseases occur mostly in patients over 60 years of age, low-dose schedules with these compounds provide a very promising approach in such patient groups by virtue of their low nonhematologic toxicity profiles. In the present review, we describe the development of treatments that target DNA hypermethylation in MDS and AML, and clinical results are presented. In addition, pharmacologic DNA demethylation may be viewed as a platform for biological modification of malignant cells to become sensitized (or resensitized) to secondary signals, such as differentiating signals (retinoids, vitamin D3) and hormonal signals (eg, estrogen receptor in breast cancer cells, androgen receptor in prostate cancer cells). Finally, an in vitro synergism between the reactivating potency of demethylating agents and inhibitors of histone deacetylation has been tested in several pilot studies of AML and MDS treatment. Finally, gene reactivation by either group of compounds results in therapeutically meaningful reactivation of fetal hemoglobin in patients with severe hemoglobinopathies, extending the therapeutic range of derepressive epigenetic agents to nonmalignant hematopoietic disorders.
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PMID:DNA methylation as a therapeutic target in hematologic disorders: recent results in older patients with myelodysplasia and acute myeloid leukemia. 1548 40

Although the first studies using DNA demethylating agents at low doses in hematologic neoplasia and hemoglobinopathies were initiated more than 20 years ago, development of this type of nonintensive treatment has only been spurred in the last 6 to 8 years by the discovery of many genes that are specifically hypermethylated in cancer. These provide a powerful rationale for using azanucleosides (and other small molecules being developed for DNA demethylation) as a novel means of pharmacologic targeting of cancer cells that is distinct from low-dose chemotherapy. Encouraging response rates of about 50% in myelodysplasia with 5-azacytidine and 5-aza-2'-deoxycytidine (decitabine or DAC) have resulted in a number of phase III studies being initiated in this disorder. The development of such drugs for the treatment of acute myeloid leukemia (AML) is ongoing. While the specificity of DNA demethylation has been delineated by studying distinct genes or sets of genes, and proof-of-principle studies of in vivo methylation report demethylation and reactivation of genes like p15/INK4b and gamma-globin, responses to demethylating agents may be more complex. Specifically, so-called cancer testis antigens (CTAs) are intriguing targets for demethylation, since they are silenced in many hematopoietic disorders and may be reactivated by epigenetic therapy. Thus, demethylating agents and histone deacetylase inhibitors may also induce a T-cell-mediated antileukemic or antitumor effect.
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PMID:Epigenetic treatment of hematopoietic malignancies: in vivo targets of demethylating agents. 1621 92

Low-dose demethylating agents such as 5-aza-2'-deoxycytidine (decitabine, DAC) and 5-azacytidine (azacitidine, Vidaza) have been explored for the treatment of myelodysplasia, acute myeloid leukemia, and hemoglobinopathies since the early 1980s, aiming to revert a methylator phenotype. Originally, the treatment rationale in hemoglobinopathies was to achieve demethylation of the hypermethylated and hence silent gamma-globin gene locus, thus reactivating synthesis of hemoglobin F (HbF). In myelodysplastic syndrome (MDS), cytogenetic analyses are mandatory for risk stratification and for monitoring response to drug treatment. The current knowledge regarding cytogenetic subgroups as predictors of response to low-dose decitabine in MDS as well as cytogenetic responses caused by demethylating agents is summarized in this review. Decitabine treatment is associated with a response rate that is higher in patients with high-risk cytogenetics (i.e., complex karyotype and/or abnormalities of chromosome 7) than in patients with intermediate-risk cytogenetics (two abnormalities or single abnormalities excluding 5q-, 20q-, and -Y). Following decitabine treatment of patients with abnormal karyotype, approximately one-third achieve a major cytogenetic response that can be confirmed by FISH analyses, while in two-thirds of patients, the abnormal karyotype persists but hematologic improvement may be observed during continued treatment. The most frequently studied gene in myelodysplasia is the cell cycle regulator p15(INK4b). Hypermethylation of p15(INK4b) in MDS is reversed during treatment with decitabine, resulting in reactivation of this gene. In hemoglobinopathies, treatment with demethylating agents leads to reactivation of fetal HbF (the gamma-globin gene locus also possibly being another target for reactivation in MDS), and thus, HbF may potentially act as surrogate marker for activity of decitabine. Other, thus far unidentified hypermethylated genes may also be targets for demethylating agents.
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PMID:In vivo effects of decitabine in myelodysplasia and acute myeloid leukemia: review of cytogenetic and molecular studies. 1629 49

Anemia can result from deficient erythropoiesis [aplastic anemia, myelodysplastic syndromes (MDS), iron deficiency anemia, anemia of chronic disease (ACD), thalassemia, megaloblastic anemia, chronic renal failure, hematological malignancies, etc.], excessive RBC destruction [hereditary spherocytosis, inherited enzyme deficiency, hemoglobinopathies, autoimmune hemolytic anemia (AIHA), paroxysmal nocturnal hemoglobinuria (PNH), etc.], and blood loss. Based on the measured red cell size(MCV), anemia is classified as microcytic, normocytic, or macrocytic. Iron parameters (serum iron, serum ferritin, etc.), reticulocyte count, bone marrow examination, Coombs test, serum vitamin B12 level, and Ham test are also useful in the differential diagnosis of anemia. Novel treatment of anemia includes lenalidomide for 5q(-)MDS, azacitidine for high-risk MDS, and eculizumab for PNH. Oral iron chelator(deferasirox) developed for the treatment of transfusional iron overload is also very useful for the management of patients with bone marrow failure syndromes.
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PMID:[Pathophysiology, diagnosis and treatment of anemia]. 1832 12


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