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

Clonal haemopoiesis has previously been demonstrated in some 30% of patients in remission of acute myeloid leukaemia (AML). Whilst a 'clonal remission' in many such patients may represent a skewed X-chromosome inactivation pattern in haemopoietic cells, its relationship to an underlying preleukaemic state remains uncertain. We therefore analysed the clonal status of 48 female patients in remission of AML using X-chromosome linked restriction fragment length polymorphisms (RFLPs) within the X-linked PGK and HPRT genes and the DXS255 (M27 beta) locus, and carried out in conjunction a detailed study of the morphological and karyotypic features of the patients' bone marrows. During remission, 35 patients (73%) with AML demonstrated nonclonal haemopoiesis, and their bone marrows were morphologically normal. Remission haemopoietic tissue in nine cases (19%) showed a skewed X-chromosome inactivation pattern and remission bone marrows in these patients had features of trilineage myelodysplasia (TMDS), with seven having similar features at presentation. Analysis of constitutional DNA showed a non-clonal pattern in seven of these patients, but was unsuccessful in two cases. These nine patients with post-chemotherapy TMDS were considered to have true clonal haemopoiesis. Four patients (8%) with a skewed X-chromosome inactivation pattern had normal remission bone marrows. Analysis of constitutional DNA showed a skewed pattern in two of these patients, but was unsuccessful in two cases. Cytogenetic investigation during remission in the nine patients with TMDS showed a normal karyotype in four cases and the acquisition of new karyotypic abnormalities in three cases. In contrast, 10 female patients in remission of de novo acute lymphoblastic leukaemia (ALL) were shown to have non-clonal haemopoiesis. We conclude that the majority of patients with AML who achieve remission after cytoreductive chemotherapy have non-clonal haemopoiesis, and when clonal remissions are observed these are commonly associated with the development of trilineage myelodysplasia in the bone marrow, with or without karyotypic abnormalities. True clonal remission in association with morphologically normal haemopoiesis is a rare entity, the significance and frequency of which remain uncertain.
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PMID:Clonal remissions in acute myeloid leukaemia are commonly associated with features of trilineage myelodysplasia during remission. 791 32

The molecular determination of the monoclonal or non-clonal nature of polycythemia cases is now possible in all or almost all females by study of the methylation pattern of several polymorphic X-linked loci. However, the techniques used are sophisticated and costly and the results do not clarify all cases. Karyotypic studies of PV, despite the number of cases reported thus far, remain insufficient. The natural history of cytogenetic events and their mechanisms of occurrence are still poorly known. Unsuccessful examinations are around 10-15%. The proportion of patients with clonal anomalies, 10-15% at diagnosis, increases with time, myelo-ablative treatments and evolution to myelofibrosis/myeloid metaplasia, so as to be close to 100% in cases with myelodysplasia/acute transformation. A few of the most frequently found non-random anomalies among which in particular trisomy 8 and 9, double trisomy 8+9, 20q- and trisomy of part or totality of 1q have some degree of specificity. Other recurring aberrations, such as 13q- mainly occur in late stages of PV, in which complex, unstable karyotypes are found. Finally none of those anomalies can be considered as a primary lesion. The frequency of clonal evolution is a matter of discussion. Despite their theoretical interest, PV cytogenetic results are of little diagnostic value, and as regards prognosis, they are statistically significant, but are of poor value in most individual patients. In conclusion, it is felt that clonality and karyotype studies should be pursued in PV, completed by "interphase cytogenetics" and molecular biology investigations, with theoretical aims rather than for immediate practical reasons.
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PMID:Clonality and karyotype studies in polycythemia vera. 803 35

The methylation pattern of three X-linked genes, phosphoglycerate kinase (PGK), hypoxanthine phosphoribosyl transferase (HPRT) and DXS255 detected by hypervariable M27 beta probe, was analysed to determine the proportion of aplastic anaemia (AA) with clonal haematopoiesis in Japanese children. Methylation analysis was performed on DNA from separated granulocytes and compared to that of bone marrow derived fibroblasts to exclude selective lyonization in all somatic cells. Of 20 female patients examined, the methylation pattern of at least one gene was informative in granulocyte DNA from 18 patients (90%). Of these, 8/20 patients (40%) were heterozygous for PGK, 8/18 (44%) were heterozygous for HPRT and 17/18 (94%) were heterozygous for DXS255. In 14/18 patients both alleles were equally methylated. Four patients exhibited a unilateral methylation pattern in their granulocytes. The same unilateral pattern was again demonstrated in fibroblasts from two of the four patients suggesting that in the latter one X chromosome was selectively inactivated in all of the somatic cells. The remaining two patients showed a unilateral methylation pattern that was restricted to their granulocytes, suggesting the existence of true clonal haematopoiesis. They responded well to antilymphocyte globulin (ALG) and presently have no evidence of a clonal disorder such as myelodysplastic syndrome (MDS) or paroxysmal nocturnal haemoglobinuria (PNH). Although these results indicate that some children with AA exhibit clonal haematopoiesis, analysis of a greater number of subjects will be required to establish the clinical value of clonal haematopoiesis in patients with AA.
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PMID:Clonal haematopoiesis in children with acquired aplastic anaemia. 833 66

Clonality in myelodysplastic syndromes (MDS) has been studied with various techniques including glucose-6-phosphate dehydrogenase (G6PD) isoenzyme and cytogenetic analyses, and with molecular techniques such as gene deletion studies and the analysis of restriction fragment-length polymorphisms (RFLP) of X-linked genes. In this study, we investigated the use of fluorescence in situ hybridization (FISH) with a chromosome-specific probe to examine cytogenetic clonality in peripheral blood (PB) cells from three patients with MDS. In each case, trisomy 8 was shown by conventional cytogenetic analysis at the time of the initial diagnosis. By using FISH with a probe for the centromere of chromosome 8, we identified the trisomy in individual PB cells from Wright-stained smears. With this technique, we could determine the cell lineage involved by the trisomy, and through serial analyses we could assess the response of the clonal and nonclonal cells to growth-factor therapy, and the expansion of the trisomic clone over time. In each of the three cases, various proportions of granulocytes, monocytes, eosinophils, and basophils showed trisomy 8 by FISH analysis. In none of the cases did we detect trisomy 8 in lymphocytes. By analysis of PB cells before and during therapy with recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF), we found that GM-CSF stimulated both trisomic and disomic cells. During a 1-year period of sequential study, we detected an abrupt increase in the percentage of trisomic cells in one patient, a stable percentage in another, and a slowly increasing percentage in the third. The abrupt increase in the first patient preceded a transformation to a more acute phase by 2 months. We conclude that FISH analysis of PB cells of patients with MDS offers an additional approach to the study of clonality in this disorder. In some cases this analysis may provide a useful and simple means of assessing response to therapy and progression of disease.
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PMID:Cytogenetic clonality in myelodysplastic syndromes studied with fluorescence in situ hybridization: lineage, response to growth factor therapy, and clone expansion. 845 4

Patients successfully treated for lymphoma by conventional cytotoxic therapy are at increased risk of developing treatment-related myelodysplasia and acute myeloid leukaemia. In this study we have investigated a group of haematologically normal females in remission from lymphoma for evidence of clonal haemopoiesis as a possible marker for the development of clonal haemopoietic disorders. Unilateral X-inactivation, and hence clonality, can be determined in females heterozygous for X-linked restriction fragment length polymorphisms by differences in methylation between active and inactive X-chromosomes. We have studied methylation patterns at the DXS255 locus and the phosphoglycerate kinase (PGK) gene in 25 females in remission from lymphoma and compared them to 35 normal females. Unilateral X-inactivation was detected in 4/15 patients in remission from lymphoma versus 2/27 normals at the DXS255 locus and in 4/13 treated lymphoma patients versus 0/11 normals at the PGK locus. Six individuals were analysed by both techniques with complete concordance. Unilateral X-inactivation was more common following cytotoxic therapy for lymphoma (7/25) than in normals (2/35) (p < 0.025) and in the lymphoma cohort was associated with increasing time from the end of therapy (p = 0.03). Patients in remission from lymphoma have an increased incidence of clonal haemopoiesis compared to normal individuals. This may be due to either the clonal expansion of an abnormal genetically damaged stem cell or a variation of normal haemopoiesis. Prospective studies will establish whether this finding is associated with an increased risk of developing treatment-related myelodysplasia and acute myeloid leukaemia.
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PMID:Clonal haemopoiesis following cytotoxic therapy for lymphoma. 850 74

Therapy-related acute myelogenous leukemia and myelodysplastic syndrome (t-AML/MDS) are being reported with increasing frequency as a complication of ABMT for Hodgkin's disease and non-Hodgkin's lymphoma. At present there is no method available to predict who is at risk or is destined to develop this nearly universally fatal disorder. We therefore investigated whether clonal growth of cells is predictive of the development of t-AML/MDS. In a patient who developed secondary AML/MDS 18 months after ABMT, X-linked clonality analysis at the human androgen receptor locus was performed on serial banked samples, and documented transition from polyclonal to clonal hematopoiesis. Clonal cells could be identified 6 months after transplant (1 year prior to the diagnosis of t-AML/MDS), at a time when there was no morphologic or clinical evidence of disease. Clonality analysis can be predictive of the development of t-AML/MDS after ABMT and may offer important insights into associated risk factors and strategies to minimize the risk of t-AML/MDS.
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PMID:Prediction of therapy-related acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) after autologous bone marrow transplant (ABMT) for lymphoma. 929 68

Clonality analysis using the polymorphism of X-linked genes, such as the phosphoglycerate kinase (PGK), hypoxanthine phosphoribosyl transferase (HPRT) genes and CAG repeat of the human androgen receptor (HU-MARA) gene and the hypervariable DXS255 gene have been widely used in the assessment of many hematologic diseases. Monoclonal hematopoiesis was clearly demonstrated in myelodysplastic syndromes (MDS), myeloproliferative disorders (MPD) and leukemia by the X-inactivation analysis. Previous studies also found a higher incidence of monoclonality in aplastic anemia and 'clonal remission' in acute leukemia. However, recent studies have shown that clonal hematopoiesis in aplastic anemia or remission of leukemia is rarer than previously thought when skewed X-inactivation was extensively ruled out by comparison with T-lymphocytes as an internal control. However, a polyclonal pattern obtained by X-inactivation cannot exclude the possibility of a small clonal cell population presenting in aplastic anemia. However, recent studies have demonstrated that residual polyclonal (possibly normal) hematopoietic progenitor cells can be detected in the bone marrow of MDS and MPD patients whose peripheral blood granulocytes showed a monoclonal pattern. This may suggest a novel approach to treatment of these diseases.
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PMID:Clonality in hematopoietic disorders. 947 67

Dyskeratosis congenita (DC) is an inherited disorder characterized by skin pigmentation, nail dystrophy and mucosal leucoplakia. In 1995 a Dyskeratosis Congenita Registry was established at the Hammersmith Hospital. In the 46 families recruited, 76/83 patients were male, suggesting that the major form of DC is X-linked. As well as a variety of noncutaneous abnormalities, the majority (93%) of patients had bone marrow (BM) failure and this was the principal cause (71%) of early mortality. In addition to BM hypoplasia, some patients also developed myelodysplasia and acute myelod leukaemia. Pulmonary abnormalities were present in 19% of patients. In affected females the phenotype was less severe. Some female carriers of X-linked DC had clinical features. Carriers of X-linked DC showed skewed X-chromosome inactivation patterns (XCIPs), suggesting that cells expressing the normal DC allele have a growth/survival advantage over cells that express the mutant allele. Linkage analysis in multiplex families confirmed that the DKC1 gene, responsible for the X-linked form of DC, is located within Xq28 and facilitated its positional cloning. The high incidence of BM failure in association with a wide range of somatic abnormalities together with the ubiquitous expression of DKC1 suggest that, as well as having a critical role in normal haemopoiesis, this gene has a key role in normal cell biology.
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PMID:Dyskeratosis Congenita (DC) Registry: identification of new features of DC. 1023 44

The chromosomal abnormality represented by an isodicentric X chromosome [idic(X)(q13)] is associated with a subset of acute myeloid leukemia (AML) and preleukemia observed in elderly females. A previous study localized the breakpoints of two acquired isodicentric X chromosomes associated with myelodysplasia to a 450-kb region proximal to the XIST gene. Here we report the construction and extensive characterization of a reliable 1-Mb P1 artificial chromosome and bacterial artificial chromosome contig covering a highly problematic region in Xq13 that includes the previously described isodicentric breakpoint region. In addition to mapping of the brain-specific gene (NAP1L2) and the phosphoglyceryl kinase alpha subunit 1 gene (PHKA1) and generation and mapping of a large number of STSs throughout the contig, we have mapped a putative transcriptional regulatory protein (HDACL1), and 35 ESTs. Sequencing data, Southern blot analysis, and fiber-FISH analysis have permitted characterization of extensive region-specific duplications and triplications in addition to an unusually high concentration of long interspersed repeat elements, both of which could be implicated in isodicentric chromosome formation and other Xq13 chromosome aberrations. FISH analysis of metaphase chromosomes from two previously unpublished AML patients and one preleukemic patient using cosmid clones and selected subclones allowed mapping of the idic(X)(q13) breakpoints to a 100-kb interval, consistent with the involvement of an X-linked gene in the genesis of this form of preleukemia, disruption of which may represent a preliminary step in progression to AML. Assembly and physical mapping of this complex 1-Mb contig establish a foundation for ongoing sequencing and gene identification projects in the region.
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PMID:Characterization of a highly complex region in Xq13 and mapping of three isodicentric breakpoints associated with preleukemia. 1075 90

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


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