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

To determine the clonal nature of hematopoiesis and to assess lineage involvement in patients with myelodysplastic syndromes (MDS), we used restriction fragment length polymorphisms of the X-linked genes phosphoglycerate kinase (PGK1) and hypoxanthine phosphoribosyltransferase (HPRT) and the X-linked probe M27 beta. Eleven female MDS patients heterozygous for at least one of these probes were studied: 3 with refractory anemia (RA), 2 with RA with ringed sideroblasts (RARS), 2 with chronic myelomonocytic leukemia (CMML), and 4 with RA with excess of blasts in transformation (RAEB-t). All exhibited clonal hematopoiesis as determined by Southern analysis of DNA prepared from peripheral blood (PB) and/or bone marrow (BM) cells. In three of the six patients heterozygous for the PGK1 gene, purified cell suspensions of polymorphonuclear cells (PMN), monocytes, lymphocytes, and/or T cells prepared from PB were tested. In addition, five of these patients were analyzed by a polymerase chain reaction (PCR)-based procedure as described recently. This method was slightly adapted to facilitate the analysis of cell lysates of fluorescence-activated cell sorted (FACS) monocytes, T and B lymphocytes, and natural killer (NK) cells. The outcome of Southern and PCR analysis was concordant, showing that PMN and monocytes were clonally derived, whereas circulating T and B lymphocytes and NK cells exhibited random X-chromosome inactivation compatible with a polyclonal pattern. To address the question of whether T cells are derived from unaffected progenitor cells or that their origin had antedated the onset of MDS, naive and memory T cells were analyzed separately. Both subsets showed a polyclonal pattern. However, in one patient analysis of constitutive DNA suggested a skewed methylation, and the presence of clonal lymphocytes against a background of polyclonal lymphoid cells cannot be ruled out in this patient. PCR analysis of PB and BM cells showed a nonrandom, unilateral pattern of X-inactivation, compatible with a mixture of clonally (myeloid) and polyclonally (lymphoid) derived cells. In conclusion, in some patients, MDS represents a disorder with clonal hematopoiesis restricted to cells of myeloid origin, whereas a random X-inactivation pattern is found in lymphoid cells.
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PMID:Clonal involvement of granulocytes and monocytes, but not of T and B lymphocytes and natural killer cells in patients with myelodysplasia: analysis by X-linked restriction fragment length polymorphisms and polymerase chain reaction of the phosphoglycerate kinase gene. 135 10

Clonal analysis of lymphocytes from patients with myelodysplastic syndrome (MDS) has been carried out using X-chromosome inactivation patterns detected by the probe M27 beta, and by polymerase chain reaction amplification of the immunoglobulin heavy chain gene hypervariable region, CDR3. Of 32 female patients heterozygous for M27 beta only seven (22%) demonstrate monoclonality of peripheral blood lymphocytes. 12 (37%) give unequivocal polyclonal results and the remaining cases give patterns of X-inactivation which cannot be interpreted either way. A study of 68 MDS patients showed five (7%) with a population of B-cells with a monoclonal rearrangement of CDR3 compared with none out of 60 normal individuals, none out of 15 with B-non Hodgkin lymphoma (B-NHL) in remission and 19 out of 25 (75%) of cases of B-chronic lymphocytic leukaemia (B-CLL). Monoclonal lymphocytes were found by both techniques in only two females with MDS. We conclude that the presence of polyclonal lymphocytes is a common finding in patients with MDS.
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PMID:Clonal lymphocytes are detectable in only some cases of MDS. 139 Feb 7

Myelodysplastic syndromes originate from a pluripotent stem cell. This view, previously suggested by G-6-PD and cytogenetic investigations, has been established unequivocally by X-chromosome inactivation analysis based on DNA polymorphisms and by studies of mutated oncogenes. Two genomic alterations associated with MDS have been analyzed in more detail. Activation of the RAS oncogenes, preferentially N-RAS, is demonstrated in approximately 35% of MDS patients. Mutations in the FMS gene, encoding the CSF-1 receptor, are found in 16% of cases. Interestingly, RAS and FMS mutations are predominantly observed in disorders of myelomonoctic differentiation, i.e., the CMML subtype in MDS and the AML FAB type M4. Moreover, homozygous deletion of the FMS gene may be an important event in the genesis of the MDS variant 5q- syndrome. Preliminary data indicate that defects in tumor-suppressor genes, namely p53, may also contribute to the development of MDS. Different lines of evidence suggest that clinical preleukemia is preceded by a phase in which genetic alterations accumulate without any hematologic change. Cases in point are the detection of RAS and FMS mutations in healthy individuals who had been treated in the past with cytotoxic therapy for lymphoma, the frequent observation of clonal remission in AML patients, or the identification of oncogene mutations in healthy individuals without even a history of malignancy or chemotherapy. Possibly, either germline mutations of oncogenes or tumor-suppressor genes and the process of genomic imprinting may constitute additional factors that predispose hematopoietic stem cells to malignant transformation. Limited as they are, the currently available data suggest that accumulation of genomic lesions, rather than their precise order of development with respect to one another, characterize the multistep process of leukemogenesis in which MDS already represent more advanced stages. The prognostic significance of oncogene mutations in MDS patients is controversially discussed. This issue awaits prospective analyses taking into account the influence of treatment modalities. However, the clinical relevance of molecularly defined parameters has already been established for their use as clonal markers in determining the mode of action and efficiency of different therapeutic approaches.
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PMID:Molecular genetic aspects of myelodysplastic syndromes. 161 6

Restriction fragment length polymorphisms (RFLP) of the X-chromosome genes phosphoglycerate kinase and hypoxanthine phosphoribosyl transferase were used in conjunction with cytogenetic analysis to study the clonality of hematopoiesis in four female patients with myelodysplastic syndromes, treated with either granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3), and in one patient with essential thrombocythemia (ET) treated with IL-3. Both conventional karyotyping and X-inactivation analysis demonstrated the persistence of a monoclonal pattern of hematopoiesis in the two patients with refractory anemia (RA) treated either with GM-CSF or with IL-3. The partial restoration of non-clonal hematopoiesis was observed in one patient with RA and an excess of blasts following treatment with a combination of GM-CSF and low dose cytosine arabinoside. In a fourth patient with RA and in the patient with ET, treatment with IL-3 resulted in the complete restoration of a non-clonal pattern of peripheral blood cells. In contrast, the bone marrow cells remained monoclonal by Southern blot analysis in the patient with RA in whom it could be tested. Non-clonal lymphocytes appear to have been released into the peripheral blood in the two latter cases and are responsible for the non-clonal RFLP pattern. These results suggest that cytokine therapy may have diverse effects on hematopoiesis, including the release of residual normal cells into the peripheral blood.
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PMID:In vivo effects of granulocyte-macrophage colony-stimulating factor and interleukin-3 on clonal and non-clonal cell populations in patients with clonal hematopoietic disorders. 167 79

Restriction fragment length polymorphisms (RFLPs) of the X-chromosome genes hypoxanthine phosphoribosyl transferase (HPRT) and phosphoglycerate kinase (PGK) were studied in 34 female patients with primary myelodysplastic syndromes (MDS). Twelve patients (35%) were heterozygous at the HPRT or PGK loci for BamHI or BglI RFLPs, respectively. In eight patients showing PGK polymorphisms, clonality was determined by X-chromosome inactivation analysis. These included patients from different morphologic subtypes: four with refractory anemia (RA), two with RA and ring sideroblasts (RARS), one patient with RA with excess of blasts (RAEB), and one with chronic myelomonocytic leukemia (CMML). A monoclonal pattern of X-chromosome inactivation was observed in seven cases. In a further case characterized by bone marrow hypoplasia, peripheral blood (PB) leukocytes were polyclonal in origin. Following low-dose cytarabine therapy, reversion to polyclonal hematopoiesis was observed in a case of RAEB indicating the presence of residual normal hematopoietic stem cells with the capacity for marrow reconstitution. The clonal relation of lymphoid and granulocyte/monocyte lineages was studied directly in two cases of CMML exhibiting somatic mutations of N-ras or Ki-ras oncogenes. By selective oligonucleotide hybridization to ras gene sequences amplified in vitro by the polymerase chain reaction, a mutated ras allele was demonstrated in PB granulocytes, monocytes, and B and T lymphocytes of both patients. We conclude that MDS arise from a multipotent hematopoietic stem cell with the potential for myeloid and lymphoid differentiation.
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PMID:Clonal analysis of myelodysplastic syndromes: evidence of multipotent stem cell origin. 256 24

A 67-year-old woman investigated because of 'myelodysplastic syndrome' was found to have a 4-fold increase in G-6-PD activity in her erythrocytes. The enzyme was partially purified and characterized. On grounds of: (a) reduced electrophoretic mobility, (b) abnormal cathodic band(s) in isoelectrofocusing, (c) increased Michaelis constant for glucose 6-phosphate, (d) abnormal thermostability, and (e) abnormal interaction with the ligand NADPH, we conclude that this is a new structural variant which we designate G-6-PD Verona. G-6-PD Verona was the sole apparent source of G-6-PD activity in the patient's erythrocytes; by contrast, the patient's fibroblasts had only normal G-6-PH (type B). The patient's haematological course terminated into acute myeloid leukaemia. We believe G-6-PD Verona was the result of a somatic mutation in an X-chromosome which took place in a haemopoietic cell clone which subsequently underwent neoplastic transformation.
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PMID:A new glucose 6-phosphate dehydrogenase variant (G-6-PD Verona) in a patient with myelodysplastic syndrome. 657 92

Clonality of marrow hematopoietic progenitor cells in myelodysplastic syndromes (MDS) was analyzed by X-chromosome inactivation pattern using polymerase chain reaction (PCR). Five female patients were included in this study; two with refractory anemia (RA) and three with RA with excess blasts (RAEB). They were heterozygous for BstXI restriction fragment length polymorphisms (RFLP) of the X-chromosome-linked phosphoglycerate kinase (PGK) gene. In each patient, erythroid and nonerythroid colonies, grown in the presence of erythropoietin and granulocyte-macrophage colony-stimulating factor (GM-CSF), exhibited no remarkable difference in clonal constitution. Two patients showed only one methylation pattern, suggesting the monoclonal origin of hematopoietic progenitor cells. Colonies of two other patients exhibited predominant and minor methylation patterns in PGK gene, indicating that nonclonal progenitor cells remain a minor population. The bone marrow of one patient appeared to contain a greater proportion of nonclonal progenitors. Stem cell factor (SCF), a potent colony-stimulating factor, enhanced both erythroid and nonerythroid colony formation. However, it did not notably alter the clonal constitutions. We conclude that nonclonal hematopoietic progenitor cells can persist in a substantial number of MDS patients.
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PMID:Evidence for nonclonal hematopoietic progenitor cell populations in bone marrow of patients with myelodysplastic syndromes. 751 21

We studied 34 patients in remission of acute myeloid leukemia (AML) by performing clonal analysis of peripheral blood polymorphonuclear (PMN) cells and mononuclear (MN) cells, using X-linked DNA polymorphisms, in conjunction with the assessment of morphological myelodysplastic changes, performed by a scoring method. Nine patients demonstrated a non-random or skewed X-chromosome inactivation pattern in PMN cells. Three of these nine patients had an apparently random pattern in MN cells (group A), whereas the remaining six patients demonstrated no difference between the inactivation patterns of PMN and MN cells (group B). The PMN cells of the other 25 patients showed a random X-chromosome inactivation pattern, and the patterns of the PMN cells did not differ from those of the MN cells (group C). The scores for myelodysplasia were high (> or = 4) in all three patients in group A, intermediate (2-3) in two patients and low (score < 2) in four patients in group B, and intermediate in five patients and low in 20 patients in group C. The duration of remission in patients with a myelodysplasia score of > or = 2 was significantly shorter than that of patients with a score of < 2 (P < 0.01). We conclude that clonal remission actually occurs with myelodysplastic features in some patients with AML (around 10%, group A). It is possible that this clonal analysis may not be sensitive enough to detect the preleukemic clone with myelodysplastic features when this clone constitutes only a minor population of remission hematopoiesis. To further elucidate the biology of such preleukemic clones it is essential to develop more sensitive molecular methods for the detection of genetic abnormalities specific to preleukemic hematopoiesis.
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PMID:Incidence and characteristics of clonal hematopoiesis in remission of acute myeloid leukemia in relation to morphological dysplasia. 756 21

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

Clonal analyses using X-chromosome inactivation patterns of the phosphoglycerate kinase (PGK) and DXS255 (M27 beta) genes were performed in women with various hematological diseases or normal hematopoiesis. Four (17%) of 24 hematologically normal females had a skewed Lyonization pattern. It, however, appeared that in the majority of cases clonality determination of myeloid cells would be possible in comparison with lymphocytes. Blasts of acute myeloid leukemia (AML) (21) and granulocytes and bone marrow cells of chronic myeloproliferative disorders (6) were all shown to be clonal, suggesting that this method was useful for the concept formation of a clonal disorder. Twelve of 14 patients with the myelodysplastic syndromes had a clonal pattern and 8 of 10 patients with aplastic anemia had a polyclonal pattern. Three of 34 patients with AML during remission were diagnosed as a clonal hematopoiesis and associated with features of myelodysplasia during remission, when clonal patterns are different in patients with the same disease, it seems important to elucidate their clinical implications.
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PMID:[Clonal study of hematopoietic cells]. 778 29


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