Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Between 1980 and 1992, 237 polycythaemic patients aged 65 or more, or with high vascular risk factors were treated with 32P according to a protocol using, or not, maintenance therapy with low-dose hydroxy-urea (500 mg/day). The present follow-up covers 1448 years/patient. Maintenance therapy was seldom discontinued because of blood toxicity or gastrointestinal intolerance, but it was stopped in 20 percent of the cases because monitoring was difficult in very old patients. Maintenance therapy reduced the mean annual 32P dose by at least 50 percent. However, the actual risk of malignant blood diseases (myelodysplasia, acute leukaemia, lymphoma) was similar in the two arms of the protocol: 14 percent at the 10th year. Compared with the French population of the same age-groups, there was no excess of epithelial cancers in both arms. Maintenance therapy did not control platelet counts perfectly. The risk of severe vascular events was identical in both arms; probably no higher than expected at that age and significantly lower than in previously published data. The actuarial survival curves in both groups showed a 50 percent survival of about 11 years, i.e. very near to that of the reference French population (12.5 years) of similar sex and age.
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PMID:[Treatment of polycythemia with 32P with or without hydroxyurea maintenance therapy. Preliminary results in 237 elderly and high vascular risk subjects studied since 1980]. 812 14

The frequent side effects of Hydroxy-Urea and the non-exceptional risk of leukemia and cancer in Polycythemia Vera treated for a long time by Hydroxy-Urea allow to conclude that Hydroxy-Urea is not an innocent drug. In a prospective trial of 150 patients with a median follow up of nine years, Hydroxy-Urea given alone induced side effects in 29% of patients necessitating to stop treatment in half of cases. The percentage of leukemia or myelodysplasia is 6.7% with an actuarial risk of leukemic transformation of 10% at 13 years. In an other prospective trial in 181 aged patients Hydroxy-Urea was given as maintenance therapy after 32P treatment. The median follow-up in that study is also of nine years. Side effects are observed in 13% of cases. A two fold increase of the leukemic risk was observed in the maintenance arm of the trial: 11 versus 19% at ten years, 14 vs 30% at 12 years, 16 vs 35% at 15 years because of the leukemogenic effect of Hydroxy-Urea in maintenance therapy we stopped including new patients in this arm of the trial.
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PMID:[Hydroxyurea--is it a harmless drug in Vaquez disease?]]. 1131 62

The p14(ARF), p15(INK4B), and p16(INK4A) genes are important negative cell-cycle regulators often inactivated by deletions, mutations, or hypermethylation in malignancy. Hypermethylation of the three genes was studied in 81 patients with therapy-related myelodysplasia (t-MDS) or acute myeloid leukemia (t-AML) by methylation-specific PCR, and p15 methylation additionally by bisulfite genomic sequencing. In all, 55 patients disclosed p15 methylation, five patients showed p16 methylation, whereas p14 methylation was not observed. Methylation of p15 was closely associated with deletion or loss of chromosome arm 7q (P=0.0006). In t-MDS, the p15 methylation frequency and the p15 methylation density both increased significantly by stage (P=0.004 and 0.0002), and p15 methylation frequency increased with an increasing percentage of myeloblasts in the bone marrow (P=0.006). In a two-variable Cox model including the percentage of myeloblasts, p15 methylation was an independent prognostic factor (P=0.005). Methylation of p15 was less common in t-AML of subtype M5 than in other FAB subtypes (P=0.03). Methylation of p15 was unrelated to type of previous therapy, to latent period from start of therapy, to platelet count, and to p53 mutations. Inactivation of p15 and deletion of genes on chromosome arm 7q possibly cooperate in leukemogenesis.
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PMID:Methylation of p15INK4B is common, is associated with deletion of genes on chromosome arm 7q and predicts a poor prognosis in therapy-related myelodysplasia and acute myeloid leukemia. 1297 Jul 81

Hypermethylation of CpG islands within the promoter region is one of the mechanisms by which genes are inactivated and may be one of the reason for silencing of cell cycle control or DNA-mismatch repair genes in myelodysplastic syndrome (MDS). Since the function of cell cycle control genes including the cyclin-dependent kinase inhibitors known as p15(INK4b) and p16(INK4a), as well as p14(ARF) which blocks MDM-2 (an inhibitor of p53), the retinoblastoma (RB1) protein and the mismatch repair gene MGMT is critical for hematopoietic proliferation and differentiation, we performed methylation specific polymerase chain reaction (MSP) in low-density, non-adherent bone marrow cells from 49 patients with MDS. In addition, expression of p15(INK4b) and RB1 was analysed by quantitative real-time PCR. From selected patients, we analyzed the methylation pattern of cell cycle control genes in CD34+ bone marrow cells. Thirty-nine of 49 cases (80%) had at least one of five genes methylated in our MDS samples by analysing low-density non-adherent bone marrow cells. The frequency of p15(INK4b) methylation was 34 of 49 samples (69%). The incidence of methylation of both p14(ARF) and p16(INK4a) was four of 49 (8%). RB1 gene was methylated in seven samples (14%) and each patient had RA. Interestingly, none of these genes were methylated in the purified CD34+ hematopoietic stem cells from the MDS patients. Furthermore, all our RARS patients had a methylated p15(INK4b) promoter correlating with non-detectable expression of this gene in bone marrow cells from those patients. These results indicate that hypermethylation of cell cycle control genes in MDS may occur late during the differentiation of myelodysplastic stem cells.
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PMID:Comparative analysis of hypermethylation of cell cycle control and DNA-mismatch repair genes in low-density and CD34+ bone marrow cells from patients with myelodysplastic syndrome. 1668 76

Erlotinib, an inhibitor of the epidermal growth factor receptor (EGFR), induces differentiation, cell-cycle arrest, and apoptosis of EGFR-negative myeloblasts of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), as well as in EGFR-negative cell lines representing these diseases (P39, KG-1, and HL 60). This off-target effect can be explained by inhibitory effects on JAK2. Apoptosis induction coupled to mitochondrial membrane permeabilization occurred independently from phenotypic differentiation. In apoptosis-sensitive AML cells, erlotinib caused a rapid (within less than 1 hour) nucleocytoplasmic translocation of nucleophosmin-1 (NPM-1) and p14(ARF). Apoptosis-insensitive myeloblasts failed to manifest this translocation yet became sensitive to apoptosis induction by erlotinib when NPM-1 was depleted by RNA interference. Moreover, erlotinib reduced the growth of xenografted human AML cells in vivo. Erlotinib also killed CD34(+) bone marrow blasts from MDS and AML patients while sparing normal CD34(+) progenitors. This ex vivo therapeutic effect was once more associated with the nucleocytoplasmic translocation of NPM-1 and p14(ARF). One patient afflicted with both MDS and non-small cell lung cancer manifested hematologic improvement in response to erlotinib. In summary, we here provide novel evidence in vitro, ex vivo, and in vivo for the potential therapeutic efficacy of erlotinib in the treatment of high-risk MDS and AML.
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PMID:Erlotinib exhibits antineoplastic off-target effects in AML and MDS: a preclinical study. 1792 89

The bone marrow is the major site of haemopoiesis in adult human. It contains cells that represent the stages in the development of different types of blood cells e.g. myelocytes, metamyelocytes, erythroblasts, reticulocytes, and other lymphoid progenies etc. Bone marrow failure is primarily the result of a specific failure of bone marrow precursor cells to produce mature cells. N-ethyl N-nitroso urea (ENU) is one of the most potent mutagens that can create an abnormal bone marrow microenvironment by causing defect in haematopoietic stem cell maturation cascade. ENU is easy to administer in mouse, and some probable mutations can be helpful to create models of human diseased conditions like Myelodysplastic syndrome (MDS). MDS is considered as an intravascular bone marrow disorder, a combined structural-functional abnormality wherein the differentiation procedure of the bone marrow stem cell is either incomplete or defective. We assumed that Myelodysplastic syndrome stands in between an inhibitory cellular pattern and a positive overshoot of abnormal differentiations representing an unknown juncture where the mystery of aplasia and leukemia hide back. Instead of using a transgenic mouse model, we attempted to develop an experimentally induced murine model of preleukemia or human MDS like disease model. In doing so ENU has been administered i.p and the animals were examined on thirtieth day and peripheral blood haemogram was documented. Upon registering the appearance of abnormal peripheral blood scenario, the changes in the intravascular bone marrow (BM) architecture, cell surface receptor expression, e.g. Sca-1, c-Kit and the early and late phase apoptic patterns were noted. The results represented an interesting correlation in between bone marrow architecture, early stem cell receptor and apoptic marker expression resembling human MDS.
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PMID:Sca-1 / c-Kit receptor expression and apoptosis pattern in ENU induced MDS mice. 2072 May 96

Stem cells are believed to be closely associated with tissue degeneration during aging. Studies of human genetic diseases and gene-targeted animal models have provided evidence that functional decline of telomeres and deregulation of cell cycle checkpoints contribute to the aging process of tissue stem cells. Telomere dysfunction can induce DNA damage response via key cell cycle checkpoints, leading to cellular senescence or apoptosis depending on the tissue type and developmental stage of a specific stem cell compartment. Telomerase mutation and telomere shortening have been observed in a variety of hematological disorders, such as dyskeratosis congenital, aplastic anemia, myelodysplastic syndromes and leukemia, in which the hematopoietic stem cells (HSC) are a major target during the pathogenesis. Moreover, telomere dysfunction is able to induce both cell-intrinsic checkpoints and environmental factors limiting the self-renewal capacity and differentiation potential of HSCs. Crucial components in the cascade of DNA damage response, including ataxia telangiectasia mutated, CHK2, p53, p21 and p16/p19(ARF), play important roles in HSC maintenance and self-renewal in the scenarios of both sufficient telomere reserve and dysfunctional telomere. Therefore, a further understanding of the molecular mechanisms underlying HSC aging may help identity new therapeutic targets for stem cell-based regenerative medicine.
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PMID:Telomere dysfunction and cell cycle checkpoints in hematopoietic stem cell aging. 2167 Oct 44

The formation of clathrin-coated vesicles is essential for intracellular membrane trafficking between subcellular compartments and is triggered by the ARF family of small GTPases. We previously identified SMAP1 as an ARF6 GTPase-activating protein that functions in clathrin-dependent endocytosis. Because abnormalities in clathrin-dependent trafficking are often associated with oncogenesis, we targeted Smap1 in mice to examine its physiological and pathological significance. Smap1-deficent mice exhibited healthy growth, but their erythroblasts showed enhanced transferrin endocytosis. In mast cells cultured in SCF, Smap1 deficiency did not affect the internalization of c-KIT but impaired the sorting of internalized c-KIT from multivesicular bodies to lysosomes, resulting in intracellular accumulation of undegraded c-KIT that was accompanied by enhanced activation of ERK and increased cell growth. Interestingly, approximately 50% of aged Smap1-deficient mice developed anemia associated with morphologically dysplastic cells of erythroid-myeloid lineage, which are hematological abnormalities similar to myelodysplastic syndrome (MDS) in humans. Furthermore, some Smap1-deficient mice developed acute myeloid leukemia (AML) of various subtypes. Collectively, to our knowledge these results provide the first evidence in a mouse model that the deregulation of clathrin-dependent membrane trafficking may be involved in the development of MDS and subsequent AML.
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PMID:Smap1 deficiency perturbs receptor trafficking and predisposes mice to myelodysplasia. 2343 93

Many cancers comprise heterogeneous populations of cells at primary and metastatic sites throughout the body. The presence or emergence of distinct subclones with drug-resistant genetic and epigenetic phenotypes within these populations can greatly complicate therapeutic intervention. Liquid biopsies of peripheral blood from cancer patients have been suggested as an ideal means of sampling intratumor genetic and epigenetic heterogeneity for diagnostics, monitoring and therapeutic guidance. However, current molecular diagnostic and sequencing methods are not well suited to the routine assessment of epigenetic heterogeneity in difficult samples such as liquid biopsies that contain intrinsically low fractional concentrations of circulating tumor DNA (ctDNA) and rare epigenetic subclonal populations. Here we report an alternative approach, deemed DREAMing (Discrimination of Rare EpiAlleles by Melt), which uses semi-limiting dilution and precise melt curve analysis to distinguish and enumerate individual copies of epiallelic species at single-CpG-site resolution in fractions as low as 0.005%, providing facile and inexpensive ultrasensitive assessment of locus-specific epigenetic heterogeneity directly from liquid biopsies. The technique is demonstrated here for the evaluation of epigenetic heterogeneity at p14(ARF) and BRCA1 gene-promoter loci in liquid biopsies obtained from patients in association with non-small cell lung cancer (NSCLC) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN), respectively.
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PMID:DREAMing: a simple and ultrasensitive method for assessing intratumor epigenetic heterogeneity directly from liquid biopsies. 2630 49

Myelodysplastic syndrome (MDS) is regarded as a spectrum of bone marrow failure disorders that share hemato-pathological state of cellular dysplasia and cytopenia. The modern treatment of cancers like chemotherapy and radiation therapy sometimes severely pounce on the basic hematopoietic stem/progenitor cellular (HSPC) compartment which gradually disclose the clinical symptoms of MDS. The present study involves flowcytometric protein expression analysis of insulin growth factor receptor (IGFR), PI3K-Akt-mTOR pathway, the autophagy related proteins (ATG's), the status of antioxidative molecules SOD2 and SDF1 and apoptosis profiling in ethyl-nitroso-urea induced myelodysplasia. The redox status that is, reactive oxygen species was estimated with dihydroetidium and the status of mitochondria and lysosomes were checked by Janus green B and neutral red staining respectively, pre and post quercetin treatment in MDS bone marrow. The results revealed the activated IGFR/PI3K/Akt axis in MDS bone marrow but unconventionally both p-mTOR and autophagy (p-ATG1, p-AT6, ATG7, ATG12) was downregulated. Interestingly, post quercetin treatment an upregulation of basal autophagocytosis, reversal of oxidative damage and proper functionality of mitochondria and lysosome was recorded. Taken together, the study hinted that the PI3K-Akt-mTOR pathway does not rule over the process of autophagocytosis in HSPC's of MDS bone marrow and the isoflavanoid quercetin remarkably restored autophagocytosis and hematopoietic oxidative status toward normalcy during the progression of myelodysplasia.
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PMID:Quercetin induces autophagy in myelodysplastic bone marrow including hematopoietic stem/progenitor compartment. 3290 6


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