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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myelodysplastic syndromes (MDS) form a heterogeneous group of clonal hematopoietic disorders with unfavourable prognosis. Allogeneic bone marrow transplantation is the only potentially curative treatment, but remains limited to a small subgroup of younger patients with HLA-compatible donors. As autologous stem cell transplantation is currently being explored as an alternative treatment strategy for MDS, more information needs to be acquired regarding the clonal nature of the progenitor cells in these autografts. Therefore, we have analyzed the clonal patterns of highly purified hematopoietic progenitors and their mature daughter cells in mobilized peripheral blood collections produced from five female patients with high-risk MDS in complete hematologic remission. X-chromosome activation patterns of flow-sorted immature (CD34 + 38low, CD34 + 33low) and committed (CD34 + 38high, CD34 + 33high) progenitors were studied with the polymerase chain reaction-based HUMARA assay. In four patients, a polyclonal remission was shown in all stem cell subpopulations and their mature daughter cells whereas one patient was found to remain skewed in all fractions, except T lymphocytes. This study provides strong evidence that polyclonal immature hematopoietic progenitors can be mobilized and harvested in patients high-risk MDS after treatment with high-dose chemotherapy.
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PMID:Polyclonal primitive hematopoietic progenitors can be detected in mobilized peripheral blood from patients with high-risk myelodysplastic syndromes. 757 31

The clonalities in white blood cells (WBC) of blood and nucleated bone marrow cells from patients with refractory anaemia and aplastic anaemia were examined by polymerase chain reaction (PCR) methods using the polymorphic short tandem repeat (STR) on the human androgen-receptor gene (HUMARA). Peripheral blood samples were obtained from 12 female patients, six with aplastic anaemia (AA) and six with refractory anaemia (RA). Peripheral blood was fractionated into granulocytes, lymphocytes, T lymphocytes and B lymphocytes. DNA was extracted from each fraction. Bone marrow samples were obtained from seven female patients (three with AA and four with RA). Sorted CD34 positive cells were cultured in a semisolid culture system. DNA was extracted from a 14-day haemopoietic colony. The clonal pattern was assessed using HUMARA gene STR polymorphism and the differential methylation pattern of nearby cytosine residues by PCR methods. Four of six (67%) AA and two of six (33%) RA patients had a monoclonal proliferating pattern in their granulocytes. The ratio of the numbers of minority colonies per majority colonies (m/M ratio) was examined for seven patients (three AA and four RA). In patients who had a clonal haemopoietic pattern in peripheral WBC the ratio was under 0.4 but not zero. In contrast, patients exhibiting a polyclonal pattern had an m/M ratio above 0.8. We concluded that some normal or heterogenous haemopoietic clones, not only MDS but also AA, may remain in the bone marrow, although almost all colonies were derived from a single pathogenic clone when the clonality pattern exhibited monoclonality in peripheral blood analysis.
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PMID:Clonal analysis of peripheral blood and haemopoietic colonies in patients with aplastic anaemia and refractory anaemia using the polymorphic short tandem repeat on the human androgen-receptor (HUMARA) gene. 777 20

Studies of X chromosome inactivation patterns are central to many aspects of our understanding of the pathogenesis of haematological malignancies. In patients with myeloproliferative disorders and myelodysplastic syndromes the demonstration of skewed X inactivation patterns in multiple haemopoietic lineages has been taken to indicate a stem cell origin for these groups of diseases. However, stem cell depletion or selection pressures can also produce skewed X inactivation patterns and might increase with age. We have therefore used the HUMARA assay to study X inactivation patterns of elderly patients with myeloproliferative disorders together with an age-matched control group of normal elderly women. A clonal pattern (clonal granulocytes and polyclonal T cells) was observed in 23.1% of normal women and 63.4% of patients with myeloproliferative disorders. This is the first report of X inactivation patterns in purified subpopulations of blood cells in normal elderly women. These results have three significant implications. Firstly, the finding of clonal granulocytes and polyclonal T cells in normal elderly women is likely to reflect age-related stem cell depletion or selection pressures. Secondly, the demonstration of clonal granulocytes and polyclonal T cells is not a useful diagnostic marker for myeloproliferative disorders or myelodysplastic syndromes in elderly women. Thirdly, our data raise the possibility that clonal blood cell patterns may precede rather than follow mutations which subsequently give rise to myelodysplastic or myeloproliferative phenotypes.
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PMID:Clonal haemopoiesis in normal elderly women: implications for the myeloproliferative disorders and myelodysplastic syndromes. 921 98

Recent studies have documented an increased risk of therapy-related myelodysplastic syndrome or acute myelogenous leukemia (t-MDS/AML) after autologous bone marrow transplant (ABMT) for non-Hodgkin's lymphoma (NHL). To develop methods to identify patients at risk for this complication, we have investigated the predictive value of clonal bone marrow (BM) hematopoiesis for the development of t-MDS/AML, as defined by an X-inactivation based clonality assay at the human androgen receptor locus (HUMARA), in a group of patients undergoing ABMT for NHL from a single institution (Dana-Farber Cancer Institute, Boston, MA). One hundred four female patients were analyzed. At the time of ABMT, the prevalence of polyclonal hematopoiesis was 77% (80/104), of skewed X-inactivation pattern (XIP) was 20% (21/104), and of clonal hematopoiesis was 3% (3/104). To determine the predictive value of clonality for the development of t-MDS/AML, a subgroup of 78 patients with at least 18 months follow-up was analyzed. As defined by the HUMARA assay, 53 of 78 patients had persistent polyclonal hematopoiesis, 15 of 78 had skewed XIP, and 10 of 78 (13.5%) either had clonal hematopoiesis at the time of ABMT or developed clonal hematopoiesis after ABMT. t-MDS/AML developed in 2 of 53 patients with polyclonal hematopoiesis and in 4 of 10 with clonal hematopoiesis. We conclude that a significant proportion of patients have clonal hematopoiesis at the time of ABMT and that clonal hematopoiesis, as detected by the HUMARA assay, is predictive of the development of t-MDS/AML (P = .004).
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PMID:Predictive value of clonality assays in patients with non-Hodgkin's lymphoma undergoing autologous bone marrow transplant: a single institution study. 961 44

The clonality of mature peripheral blood-derived myeloid and lymphoid cells and bone marrow haemopoietic progenitors from 18 females with myelodysplasia (MDS) (five refractory anaemia, RA; one RA with ringed sideroblasts, RARS; three chronic myelomonocytic leukaemia, CMML; four RA with excess of blasts, RAEB; five RAEB in transformation, RAEB-t) was studied by X-chromosome inactivation analysis. Using the human androgen-receptor (HUMARA) assay, we analysed the clonal patterns of highly purified immature CD34+ 38- and committed CD34+ 38+ marrow-derived progenitors, and CD16+ 14- granulocytes, CD14+ monocytes, CD3+ T and CD19+ B lymphocytes from peripheral blood. In high-risk patients (RAEB, RAEB-t), clonality analysis was performed before and after intensive remission-induction treatment. All patients, except one with RA, had predominance of a single clone in their granulocytes and monocytes. The same clonal pattern was found in CD34+ progenitor cells. In contrast, CD3+ T lymphocytes were polyclonal or oligoclonal in 14/18 patients. X-chromosome inactivation patterns of CD19+ B cells were highly concordant with CD3+ T cells except for two patients (one RA, one CMML) with monoclonal B and polyclonal T lymphocytes, therefore suggesting a clonal mutation in a progenitor common to the myeloid and B-lymphoid lineages or the coexistence of MDS and a B-cell disorder in these particular patients. After high-dose non-myeloablative chemotherapy, polyclonal haemopoiesis was reinstalled in the mature myeloid cells and immature and committed marrow progenitors in three of four patients achieving complete haematological remission. Therefore we conclude that most haematological remissions in MDS are associated with restoration of polyclonal haemopoiesis.
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PMID:Patients with high-risk myelodysplastic syndrome can have polyclonal or clonal haemopoiesis in complete haematological remission. 969 63

The human androgen-receptor gene (HUMARA) has been used for analysis of X chromosome inactivation (XCI) pattern because of a polymorphic short tandem repeat (STR) near the 5'-promoter region correlated with XCI. We introduce a novel method to analyze XCI pattern, named HUMARA methylation-specific PCR (HUMARA-MSP) assay, which analyzes methylation status of the HUMARA gene by bisulfite modification instead of a methylation-sensitive restriction enzyme. Although the original MSP method shows whether there is a methylated band or not, our HUMARA-MSP method identifies the patterns of methylated and unmethylated bands. Because this method identifies either unmethylated or methylated alleles in each PCR tube and shows opposite band patterns dependent on methylation status, we can assess the XCI pattern independently twice. This method can avoid false results by incomplete enzyme digestion and incomplete bisulfite modification will not affect the results. Extremely small quantities of samples, such as hematopoietic colonies, were also available for HUMARA-MSP assay. Because DNA modified by sodium bisulfite is also available for assessment of methylation status of other genes by setting specific primers for them, we performed the simultaneous assessment of clonality and aberrant hypermethylation of p15INK4B gene in myelodysplastic syndromes. These simultaneous assessments were easily possible and provided much information despite requiring only a small volume of DNA. The HUMARA-MSP assay may facilitate the analyses for pathogenesis of hematological disorders because of its simplicity, sensitivity and wide applicability. Leukemia (2000) 14, 207-212.
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PMID:Clonality analysis by methylation-specific PCR for the human androgen-receptor gene (HUMARA-MSP). 1063 97

We previously reported that the hypermethylation of the p15INK4B gene promoter was frequently observed in myelodysplastic syndromes (MDS), and that it may be associated with disease progression. An unanswered question is whether p15INK4B gene methylation is restricted to undifferentiated blastic cells, or whether differentiated cells such as granulocytes or erythrocytes of MDS origin also harbor this epigenetic alteration. In this study, we analyzed the methylation status of the p15INK4B gene in MDS by the methylation-specific PCR (MSP) method, which is more sensitive than Southern blotting. The bone marrow mononuclear cells (BM-MNCs) of 23 MDS patients were analyzed, and six of them showed p15INK4B methylation. Progenitor assay with methylcellulose medium was also performed in all patients. In two of the six patients with p15INK4B-methylated BM-MNCs, erythroid and/or non-erythroid colonies formed were subjected to molecular analysis. Colonies with and without p15INK4B methylation were detected in both patients. Furthermore, X-chromosome inactivation (XCI) pattern of each colony was simultaneously determined by MSP-based human androgen receptor gene analysis (HUMARA-MSP), and all p15INK4B-methylated colonies showed the same XCI pattern, which was dominant among the colonies, while p15INK4B-unmethylated colonies showed both patterns of XCI, in each of the two patients. We then examined the methylation status of the p15INK4B gene of granulocyte (PB-PMN) fractions from 10 patients with available peripheral blood cells. In all four patients with p15INK4B-methylated BM-MNCs, their PB-PMNs showed p15INK4B methylation. These results suggest that p15INK4B methylation in hematopoietic cells in MDS patients is restricted to the MDS clone but not necessarily to blast cells.
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PMID:Methylation status of the p15INK4B gene in hematopoietic progenitors and peripheral blood cells in myelodysplastic syndromes. 1076 43

Bone marrow and peripheral blood from a myelodysplastic syndrome patient with trisomy 13 and monoclonal B lymphocytes (without evidence of systemic lymphoma) were investigated for clonal lymphoid lineage involvement using interphase fluorescence in situ hybridization (FISH) and X-chromosome inactivation assay (HUMARA) on CD19+ and CD34+ sorted cells. Trisomy 13 was detected in 55% of CD34+ cells and in 5.5% of CD19+ cells, the latter being comparable to the negative control specimen. X-chromosome inactivation showed both CD34+ and CD19+ cells to be monoclonal, though their inactivated X-chromosome was different. The results strongly suggested that both populations of CD34+ and CD19+ cells have originated from a different progenitor stem cell.
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PMID:Simultaneous occurrence of myelodysplastic syndrome and monoclonal B lymphocytes with a different clonal origin. 1190 28

It is well known that some patients with monopathic thrombocytopenia in myelodysplastic syndrome (MDS) show clinico-hematologic features resembling chronic idiopathic thrombocytopenic purpura (ITP). This study examined the monoclonal nature of ITP to obtain a further insight into patients with borderline ITP and monopathic thrombocytopenia in MDS, using polymorphic trinucleotide CAG repeats in the X-linked human androgen receptor (HUMARA) gene. In this study, we separated peripheral neutrophils and mononuclear cells (MNCs) from 18 patients with chronic ITP, and analyzed them in comparison with those from normal or MDS female subjects by PCR-based HUMARA assay. All normal controls showed a polyclonal pattern of the HUMARA gene, whereas some MDS patients had monoclonality in MNC and/or neutrophils. Among ITP patients, two had a nonrandom inactivation pattern of the HUMARA gene in neutrophils, which was considered to be derived from hematopoietic cells of clonal origin, whereas no ITP patient had MNC of clonal nature. Two ITP patients with a monoclonal pattern in the neutrophil fraction were refractory to ordinary treatment. This approach may provide further information in patients with borderline hematologic disorders between chronic ITP and refractory thrombocytopenia of MDS.
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PMID:Monoclonal constitution of neutrophils detected by PCR-based human androgen receptor gene assay in a subset of idiopathic thrombocytopenic purpura patients. 1212 51

Chronic myelogenous leukemia (CML) is characterized by the presence of a Bcr-Abl fusion protein with deregulated tyrosine kinase activity that is required for maintaining the malignant phenotype. Imatinib, a selective inhibitor of Bcr-Abl, induces major cytogenetic remission (MCR) or complete cytogenetic remission (CCR) in the majority of patients with CML in first chronic phase. However, thorough re-evaluation of cytogenetics in a cohort of patients in MCR or CCR demonstrated clonal karyotypic abnormalities in more than 10% of cases, some of which were clinically associated with a myelodysplastic syndrome (MDS). Further analysis identified previous exposure to cytarabine and idarubicin as significant risk factors for the subsequent occurrence of abnormalities in Philadelphia chromosome-negative (Ph-) cells. To investigate if cytogenetically normal but clonal hematopoiesis might be present in other patients in cytogenetic remission, we studied X-chromosome inactivation as a marker of clonality by polymerase chain reaction analysis of the human androgen receptor (HUMARA). We find that imatinib restores a polyclonal pattern in most patients in CCR and MCR. Nonetheless, our results are consistent with the notion that targeted therapy of CML with imatinib favors the manifestation of Ph- clonal disorders in some patients. They indicate that patients on imatinib should be followed with conventional cytogenetics, even after induction of CCR.
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PMID:Emergence of clonal cytogenetic abnormalities in Ph- cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. 1450 73


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