UMLS:C0026986 - FACTA Search

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

The t(3;21)(q26;q22) is a recurring chromosomal abnormality in blastic crisis of chronic myelogenous leukemia (CML) and in therapy-related myelodysplastic syndrome and acute leukemia. In order to clarify the genetic recombination mechanism underlying the t(3;21), we molecularly cloned the breakpoints and determined their nucleotide sequence in a case of CML in blastic crisis with t(3;21). Near the breakpoint on chromosome 21, three homopyrimidine (CT)-rich sequences were found. We also identified a sequence homologous to the topoisomerase II binding and cleavage consensus sequence surrounding the breakpoint on chromosome 3, and two topoisomerase II binding and cleavage consensus sequences near the breakpoint on chromosome 21. In addition, around the breakpoint on chromosome 21, four chi-like sequences, potential consensus signals for activating recombination, were found. There were no Alu sequences or antigen receptor gene-like heptamer/nonamer signal sequences within the breakpoints on chromosomes 3 and 21. The breakpoints were found adjacent to the topoisomerase II binding and cleavage consensus sequence or the homopyrimidine-rich sequence. Furthermore, the chi-like sequences and the homopyrimidine-rich sequence were detected on chromosome 21 but not on chromosome 3. Genes Chromosomes Cancer 26:92-96, 1999.
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PMID:Molecular characterization of the genomic breakpoints in a case of t(3;21)(q26;q22). 1044 Oct 11

Translocation t(11;21)(q24;q11.2) is a rare but recurrent chromosomal abnormality associated with myelodysplastic syndrome (MDS) that until now has not been characterized at the molecular level. We report here results of a molecular cytogenetic analysis of this translocation in a patient with refractory anemia. Using FISH with a panel of 11q and 21q cosmid/YAC probes, we localized the chromosome 11 breakpoint at q23.3 in a region flanked by CP-921G9 and CP-939H3 YACs, distal to the HRX/MLL locus frequently involved in acute leukemias. The chromosome 21 breakpoint was mapped in a 800-kb fragment inserted into the CP-145E3 YAC at 21q11.2, proximal to the AML1 gene. It is noteworthy that in all four cases with a t(11;21) reported until now, a second der(11)t(11;21) and loss of normal chromosome 11 could be observed either at diagnosis or during the course of the disease. Since in our case heteromorphism was detected by FISH on the centromeric region of the two der(11), the second der(11) chromosome could be the result of a mitotic recombination that had occurred on the long arm of chromosome 11, rather than of duplication of the original der(11). Constancy of secondary karyotypic changes resulting in an extra copy of the putative chimeric gene at der(11), loss of 11 qter sequences, and partial trisomy 21 suggest that neoplastic progression of MDS cases with a t(11;21) may be driven by the same mechanism(s).
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PMID:Molecular cytogenetics localizes two new breakpoints on 11q23.3 and 21q11.2 in myelodysplastic syndrome with t(11;21) translocation. 1045 99

Spectral karyotyping (SKY) is a new molecular cytogenetic technique that allows simultaneous visualization of each chromosome in a different color. We have used SKY for comprehensive analysis of 20 myelodysplastic syndromes (MDSs) (13 primary MDSs, 3 therapy-related MDSs, and 4 acute leukemias developed from MDS, including 1 cell line established from a secondary leukemia), previously analyzed by G-banding. To locate the chromosomal breakpoints, DAPI-counterstained band images from all metaphases were transformed to G-band-like patterns. By using SKY, it was possible to identify the origin and organization of all clonal marker chromosomes (mar), as well as the origin of all abnormalities defined as additional material of unknown origin (add) or homogeneously staining regions (hsr) by G-banding. In total, SKY identified the chromosomal basis of 38 mar, add, and hsr, corrected 8 abnormalities misidentified by G-banding, and revealed 6 cryptic translocations in 5 cases. Total or partial chromosomal loss (mainly of -5/5q- and -7/7q-) is the most frequent cytogenetic abnormality in MDS. In 3 of 11 cases with -5/5q- and in 4 of 8 with -7/7q-, lost material was detected by SKY in unbalanced translocations. A total of 60 chromosomal losses were identified by G-banding in 16 cases with multiple chromosome abnormalities involving at least 3 chromosomes. For 26 of these losses (43%), SKY analysis suggested that the losses were not complete, but had been translocated to a variety of partner chromosomes. Moreover, SKY analysis revealed that a ring chromosome in a case of acute leukemia developed from MDS contained three to six segments that originated from chromosome 21 material. Fluorescence in situ hybridization showed the amplification of the AML1 gene on regions derived from chromosome 21, providing the first evidence of amplification involving this gene in MDS. Genes Chromosomes Cancer 26:336-345, 1999.
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PMID:Combined spectral karyotyping and DAPI banding analysis of chromosome abnormalities in myelodysplastic syndrome. 1053 69

Granulocyte colony-stimulating factor (G-CSF) has had a major impact on management of "severe chronic neutropenia," a collective term referring to congenital, idiopathic, or cyclic neutropenia. Almost all patients respond to G-CSF with increased neutrophils, reduced infections, and improved survival. Some responders with congenital neutropenia have developed myelodysplastic syndrome and acute myeloblastic leukemia (MDS/AML), which raises the question of the role of G-CSF in pathogenesis. The Severe Chronic Neutropenia International Registry (SCNIR), Seattle, WA, has data on 696 neutropenic patients, including 352 patients with congenital neutropenia, treated with G-CSF from 1987 to present. Treatment and patient demographic data were analyzed. The 352 congenital patients were observed for a mean of 6 years (range, 0.1-11 years) while being treated. Of these patients, 31 developed MDS/AML, for a crude rate of malignant transformation of nearly 9%. None of the 344 patients with idiopathic or cyclic neutropenia developed MDS/AML. Transformation was associated with acquired marrow cytogenetic clonal changes: 18 patients developed a partial or complete loss of chromosome 7, and 9 patients manifested abnormalities of chromosome 21 (usually trisomy 21). For each yearly treatment interval, the annual rate of MDS/AML development was less than 2%. No significant relationships between age at onset of MDS/AML and patient gender, G-CSF dose, or treatment duration were found (P >.15). In addition to the 31 patients who developed MDS/AML, the SCNIR also has data on 9 additional neutropenic patients whose bone marrow studies show cytogenetic clonal changes but the patients are without transformation to MDS/AML. Although our data does not support a cause-and-effect relationship between development of MDS/AML and G-CSF therapy or other patient demographics, we cannot exclude a direct contribution of G-CSF in the pathogenesis of MDS/AML. This issue is unclear because MDS/AML was not seen in cyclic or idiopathic neutropenia. Improved survival of congenital neutropenia patients receiving G-CSF therapy may allow time for the expression of the leukemic predisposition that characterizes the natural history of these disorders. However, other factors related to G-CSF may also be operative in the setting of congenital neutropenia. (Blood. 2000;96:429-436)
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PMID:Myelodysplasia syndrome and acute myeloid leukemia in patients with congenital neutropenia receiving G-CSF therapy. 1088 2

The AML1 gene, situated in 21q22, is often rearranged in acute leukemias through t(8;21) translocation, t(12;21) translocation, or less often t(3;21) translocation. Recently, point mutations in the Runt domain of the AML1 gene have also been reported in leukemia patients. Observations for mutations of the Runt domain of the AML1 gene in bone marrow cells were made in 300 patients, including 131 with acute myeloid leukemia (AML), 94 with myelodysplastic syndrome (MDS), 28 with blast crisis chronic myeloid leukemia (CML), 3 with atypical CML, 41 with acute lymphoblastic leukemia (ALL), and 3 with essential thrombocythemia (ET). Forty-one of the patients had chromosome 21 abnormalities, including t(8;21) in 6 of the patients with AML, t(12;21) in 8 patients with ALL, acquired trisomy 21 in 17 patients, tetrasomy 21 in 7 patients, and constitutional trisomy 21 (Down syndrome) in 3 patients. A point mutation was found in 14 cases (4.7%), including 9 (22%) of the 41 patients with AML of the Mo type (MoAML) (none of them had detectable chromosome 21 rearrangement) and 5 (38%) of the 13 myeloid malignancies with acquired trisomy 21 (1 M1AML, 2 M2AML, 1 ET, and 1 atypical CML). In at least 8 of 9 mutated cases of MoAML, both AML alleles were mutated: 3 patients had different stop codon mutations of the 2 AML1 alleles, and 5 patients had the same missense or stop codon mutation in both AML1 alleles, which resulted in at least 3 of the patients having duplication of the mutated allele and deletion of the normal residual allele, as shown by FISH analysis and by comparing microsatellite analyses of several chromosome 21 markers on diagnosis and remission samples. In the remaining mutated cases, with acquired trisomy 21, a missense mutation of AML1, which involved 2 of the 3 copies of the AML1 gene, was found. Four of the 7 mutated cases could be reanalyzed in complete remission, and no AML1 mutation was found, showing that mutations were acquired in the leukemic clone. In conclusion, these findings confirm the possibility of mutations of the Runt domain of the AML1 gene in leukemias, mainly in MoAML and in myeloid malignancies with acquired trisomy 21. AML1 mutations, in MoAML, involved both alleles and probably lead to nonfunctional AML1 protein. As AML1 protein regulates the expression of the myeloperoxidase gene, the relationship between AML1 mutations and Mo phenotype in AML will have to be further explored. (Blood. 2000;96:2862-2869)
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PMID:High incidence of biallelic point mutations in the Runt domain of the AML1/PEBP2 alpha B gene in Mo acute myeloid leukemia and in myeloid malignancies with acquired trisomy 21. 1102 23

We present a 26-year-old patient with myelodysplastic syndrome (MDS). Initial bone marrow cytogenetics with G-banding showed a rearranged chromosome 21, which was dicentric and bisatellited on CBG- and NOR-banding. Fluorescence in situ hybridization helped to characterize the structure, using a whole chromosome 21 paint and the locus specific AML1 gene probe. The rearranged 21 consisted solely of chromosome 21 material, contained only one copy of AML1, and was not a trisomy, but a deleted tandem translocation. The MDS transformed to acute myeloid leukemia (AML), and the patient died almost 12 months post-diagnosis. Cytogenetics was performed three times during the course of the disease, and the dicentric chromosome 21 was present throughout. Although there are a number of published rearrangements of chromosome 21 in MDS and AML, most are isodicentrics. We could not find another case of an abnormal chromosome 21 with the same structure as reported here.
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PMID:A novel dicentric deleted chromosome 21 arising from tandem translocation. 1106 10

In the genesis of hematologic neoplasms gene amplification is a mechanism for illegitimate activation of proto-oncogenes. We report a phenotypically normal patient with a constitutional ring chromosome 21 who developed acute myeloid leukemia (AML). The leukemic cells revealed size-variable ring chromosomes 21 with amplification of the proto-oncogene AML1, located in the chromosomal band 21q22, within the rings. Hitherto, amplification of the proto-oncogene AML1-also in form of a ring chromosome-has been described recently only in one patient with myelodysplastic syndrome (MDS). In AML, gene amplification by ring formation has been demonstrated only in another three patients (amplification of the MLL gene in two cases and of the ETV6 gene in one case). Here we present the new evidence that the internal rearrangement of a constitutional ring chromosome 21 resulted in multiplication of a proto-oncogene in bone marrow cells and provided obviously a selective growth advantage. Moreover the amplification of ribosomal DNA was observed in the ring chromosomes of the tumor cells.
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PMID:Amplification of the AML1(CBFA2) gene on ring chromosomes in a patient with acute myeloid leukemia and a constitutional ring chromosome 21. 1116 21

The pattern of occurrence of malignant disorders in people with Down's syndrome (DS) is unique and may serve as a model in the search for leukaemogenic genes and tumour suppressor genes on chromosome 21, since the risk of leukaemia is higher in individuals with DS than in non-DS individuals. Acute lymphoblastic leukaemia in DS shares many of the clinical characteristics of the same malignancy in other patients, and with current intensive therapy the long-term survival is similar. Myelodysplastic syndrome and acute myeloid leukaemia have unique clinical characteristics in these patients and are best described as a single disorder, termed myeloid leukaemia of DS. When these patients are treated intensively, they show better survival rates than patients without DS. This may be related to increased expression of genes on chromosome 21 contributing to increased chemosensitivity. Chronic myeloid leukaemia and chronic lymphocytic leukaemia occur less often than expected. With the exception of an increased risk of retinoblastoma, germ-cell tumours, and perhaps lymphomas, the risk of developing solid tumours is lower in both children and adults. Breast cancer is almost absent, and the risk of a second malignant disease after treatment for leukaemia also appears to be decreased. Increased susceptibility to apoptosis in DS may result in cell death rather than malignant transformation after major cell injuries. This hypothesis would explain the decreased risk of both solid tumours and secondary cancers.
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PMID:Pattern of malignant disorders in individuals with Down's syndrome. 1190 37

A new t(20;21)(q11;q11), associated with a deletion on the long arm of chromosome 20, was found in one patient with an acute myelocytic leukemia (AML) and in one with myelodysplastic syndrome (MDS). In both cases deletion was interstitial, extending from band q11 to band q13, as shown by comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH). FISH analysis with whole arm paints, subtelomeric probes, and locus-specific probes for the long arms of chromosomes 20 and 21 revealed in patient 1 a reciprocal translocation between the deleted 20q and the long arm of chromosome 21, that is, del(20)(q11q13)t(20;21)(q11;q11), and in patient 2, material from 21q was inserted into the deleted 20q, that is, del(20)(q11q13)ins(20;21)(q11;q11q22). This is the first identification of a complex 20;21 rearrangement in MDS/AML. Deletion at 20q and juxtaposition between 20q11 and 21q11 appear to be the critical genomic events.
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PMID:Different mechanisms lead to a karyotypically identical t(20;21) in myelodysplastic syndrome and in acute myelocytic leukemia. 1255 Jul 52

Familial platelet disorder with propensity to acute myelogenous leukemia, or FPD/AML (OMIM #601399), is a rare autosomal dominant condition, with only 12 families reported. It is characterized by qualitative and quantitative platelet defects and predisposition to the development of myeloid malignancies. Causal mutations have been identified in the RUNX1 gene (also known as AML1, CBFA2) in the 11 families so far analyzed. RUNX1 is a gene frequently involved in the pathogenesis of sporadic leukemia and myelodysplastic syndromes, through acquired chromosome rearrangements and point mutations. We report an Italian family with three members affected with FPD/AML, two sibs and their father, who developed myelodysplastic syndromes (which in one subsequently evolved into AML). Direct sequencing and polymorphisms haplotype analysis of the region of chromosome 21 where RUNX1 is mapped demonstrated that FPD/AML in this family was not caused by any mutation of the RUNX1 gene, thus providing evidence for the genetic heterogeneity of this disorder. Cytogenetic studies showed monosomy 7 in the marrow of all the three affected subjects, as well as an independent clone with trisomy 8 in the father. The importance of mutator effects in the pathogenesis of familial myeloid malignancies characterized by relevant chromosome changes, in the presence or absence of an underlying Mendelian disorder, has already been suggested. Our results and a review of the cytogenetic literature led us to postulate that mutations also causing FPD/AML may have a mutator effect that could give origin to myelodysplastic syndromes and acute myeloid leukemias through acquired chromosome changes.
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PMID:Familial platelet disorder with propensity to acute myelogenous leukemia: genetic heterogeneity and progression to leukemia via acquisition of clonal chromosome anomalies. 1513 96

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