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

We used a sensitive, quantitative bisulfite PCR assay, methylation sensitive single nucleotide primer extension (Ms-SNuPE), to measure methylation of the 5' CpG islands of c-abl and p15 in chronic myelogenous leukemia (CML) patients during progression. We found that the Pa promoter of c-abl was methylated in 81% (17/21) of the white blood cells (WBCs) of CML patients, which correlates with previous reports. In contrast, WBCs from healthy donors, acute myelogenous leukemias, acute lymphocytic leukemias, and myelodysplastic syndromes were unmethylated at the c-abl Pa promoter locus. We also observed p15 hypermethylation in 24% (8/34) of CML cases. Methylation of the p15 but not c-abl Pa promoters was associated with CML progression (P = 0.047 vs 0.46), and the two events were independently acquired. We conclude that de novo methylation of c-abl and p15 both occur in CML, and analysis of DNA methylation changes using the bisulfite-based MS-SNuPE assay allows both a sensitive and quantitative assessment of these molecular events compared to other methods currently utilized. (Blood. 2000;95:2990-2992)
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PMID:Quantitative measure of c-abl and p15 methylation in chronic myelogenous leukemia: biological implications. 1077 50

We report a case of de novo acute myelomonocytic leukaemia with the t(2;11)(q31;p15) translocation in a Japanese female infant. The NUP98-HOXD13 fusion transcript generated by the translocation was detected in the patient's bone marrow cells by reverse transcription-polymerase chain reaction (RT-PCR). Additionally, ectopic expression of the normal allele of the HOXD13 gene was observed in this patient, suggesting that it might be associated with leukaemogenic development. This case is the third report of t(2;11) leukaemia with NUP98-HOXD13 and the first report showing that NUP98 rearrangements are associated with infant leukaemia, as well as therapy-related acute myelogenous leukaemia or myelodysplastic syndrome.
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PMID:Generation of the NUP98-HOXD13 fusion transcript by a rare translocation, t(2;11)(q31;p15), in a case of infant leukaemia. 1093 Oct

We report a boy with Down's syndrome (DS) who developed myelodysplastic syndrome (MDS) after spontaneous remission of transient myeloproliferative disorder (TMD) at birth. Chromosomal analysis of the blasts in the MDS phase demonstrated t(7;11)(p13;p14) which had not been detected in the TMD phase. NUP98-HOXA9 chimera mRNA, which is known to be involved in t(7;11)(p15;p15) translocation in acute myeloid leukemia (AML), was not detected by reverse transcriptase-polymerase chain reaction, and NUP98 rearrangement was not detected by Southern blot analysis of the blasts in the MDS phase. Reciprocal translocation is very rare in AML/MDS in DS, and the t(7;11)(p13;p14) found in our patient was different from the recurrent translocation t(7;11)(p15;p15) previously reported.
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PMID:Down's syndrome with myelodysplastic syndrome showing t(7;11)(p13;p14). 1093 66

Chromosomal aberrations are frequently associated with therapy-related myelodysplastic syndromes and acute myelogenous leukemia (t-MDS/AML) and are thought to result from exposure to genotoxic drugs, including alkylating agents and DNA topoisomerase II poisons. The NUP98 gene on chromosome band 11p15 is involved in several different chromosomal aberrations that have been associated with t-MDS/AML. We have cloned the translocation breakpoints from two cases of t-MDS harboring a t(11;20)(p15;q11). Sequence analysis of the breakpoints from both cases revealed almost perfectly balanced translocations between NUP98 and TOP1. There were no known recombinogenic sequences identified at or near the breakpoints. However, four bp microduplications present at the translocation crossover points suggested that these translocations may have been initiated by 4 bp staggered double-stranded DNA breaks, which are known to be associated with the action of topoisomerase II. Given the history of patient exposure to topoisomerase II poisons, and the fact that these drugs stabilize staggered breaks with a 4 bp overhang, it seems possible that drug-induced topoisomerase II cleavage and subunit exchange was involved in these translocations. These results suggest that NUP98 is a recurrent target for therapy-related malignancies induced by multiagent chemotherapy, and suggest a role for DNA topoisomerase II poisons in the generation of these translocations. Published 2000 Wiley-Liss, Inc.
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PMID:Potential role for DNA topoisomerase II poisons in the generation of t(11;20)(p15;q11) translocations. 1095 88

Several studies have demonstrated the prognostic value of cytogenetic analysis in MDS both for survival and progression to AML. However it is unknown which are the numerical or structural abnormalities required for leukemic transformation. In this report we studied clinically and cytogenetically 127 patients: 125 with primary MDS and two with AML with a previous history of MDS. Thirty-one patients (24%) showed evolution of the disease during the follow-up study. Chromosomal abnormalities found at diagnosis in patients that progressed toward AML included: del(5)(q15), +6, del(6)(q21), t(5;8)(q32;q22),-7, del(7)(q22), der(7)t(1;7)(q10;p10), t(7;11)(p15;p15), +8, del(11)(q23), del(12p), del(3)(q21), del(20)(q12) and complex karyotypes. Eight of these patients were studied cytogenetically during transformation and showed acquisition of chromosomal alterations involving dup(1q), +8, del(11)(q23), and translocations between chromosomes 1 and 8 or 7 and 17. In addition we also observed gain of ploidy and monosomy 21. These results suggest that chromosomal alterations during evolution of the disease include special chromosome gains or abnormalities of chromosomes 1, 7, 8, 11 and 17 with involvement of ETV-1, Hox-A9, Pax 4, MLL genes besides a putative gene mapped at 17q25. We also applied the International Prognostic Scoring System (IPSS) to 114 patients, excluding those submitted to allogeneic bone marrow transplant. Our patients were classified into four distinct risk groups. The analysis of risk groups presented by 27 patients who showed evolution of the disease revealed 18 at the high risk group and four at the intermediate-2 group. From the intermediate-1 risk group only five patients showed evolution of the disease. Three of these patients evolved from RA to RAEB with gain of a del(11)(q23) or an expansion of a del(12)(p12) clone. Our results suggest that some chromosomal alterations are responsible for each step in the evolution of the disease. As the pathway of evolution is not unique it has been very difficult to define what genetic alteration comes first. However from several results in the literature and our own, it seems that some chromosomal alterations may predict the evolution of the disease and are correlated with short survival, as for example the trisomy of chromosome 8, and might be incorporated in the high risk group in the IPSS. This score system has been proved to be useful for predicting survival and evolution from MDS to AML.
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PMID:Chromosomal alterations associated with evolution from myelodysplastic syndrome to acute myeloid leukemia. 1099 2

The role of the BCR-ABL fusion gene in the pathogenesis of the chronic phase of chronic myelogenous leukemia (CML) has been well established. Several additional genetic changes have been reported to occur, at varying frequencies, during disease progression to "accelerated" and "blast crisis" phases. The NUP98 gene localized to chromosome band 11p15 has been found at the breakpoints of several distinct chromosomal translocations in patients with both de novo and therapy-related myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). Using combined cytogenetic and molecular analyses, we have found rearrangements of the NUP98 gene in the leukemic cells of two patients with Philadelphia chromosome-positive CML, during disease evolution. As expected, analysis of the t(7;11)(p15;p15) from one of the patients showed an in-frame NUP98-HOXA9 fusion. The fusion points were similar to previously reported NUP98-HOXA9 fusion points from patients with MDS/AML. Our results indicate that the NUP98 gene is an additional, albeit infrequent, genetic target during clonal evolution of CML.
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PMID:NUP98 gene rearrangements and the clonal evolution of chronic myelogenous leukemia. 1124 95

We report herein a 38-year-old male patient with Fanconi anemia but with few phenotypic manifestations--short stature, sterility, and hypoplasic anemia with several years of evolution-who developed a myelodysplastic syndrome (MDS). Bone marrow karyotype showed long arm triplication of chromosome 1 (q12-21q31-q32), and two markers add(11)(p15) and add(21)(q22) which had extra material of chromosome 3 besides the normal chromosome 3 pair. Peripheral blood showed chromosome instability; SCE was normal. Both the patient and his family showed a high prevalence of malignant diseases. 1q duplication and, in a few cases, triplication of 1q has been related to Fanconi anemia, being of unknown significance.
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PMID:Triplication of 1q in Fanconi anemia. 1140 63

In myelodysplastic syndrome (MDS), the expression of the cyclin-dependent kinase inhibitor p15(ink4B) (p15) is frequently decreased because of the aberrant methylation of the gene promoter; p15 is normally up-regulated during megakaryocytic differentiation. It was hypothesized that p15 methylation and deregulation of gene expression contribute to defective megakaryocytopoiesis in patients with MDS. Here it is shown that the increasing autocrine production of TGF-beta1 stimulates megakaryocytic differentiation in normal CD34(+) cells and that p15 mediates, at least in part, this effect. This TGF-beta1-dependent pathway is altered in MDS CD34(+) progenitors because of p15 methylation. The demethylating agent 2-deoxyAZAcytidin can restore the normal demethylated state of the p15 gene and increase its expression. Nevertheless, MDS CD34(+) cells only poorly differentiate to the megakaryocytic lineage. These findings suggest that p15 methylation occurs in a neoplastic clone with a profound defect of cell proliferation, survival, and differentiation that cannot be overcome by using a demethylating drug.
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PMID:Expression of p15(ink4b) gene during megakaryocytic differentiation of normal and myelodysplastic hematopoietic progenitors. 1143 25

Cytogenetic abnormalities are seen in approximately 50% of cases of myelodysplastic syndrome (MDS) and 80% of cases of secondary MDS (following chemotherapy or radiotherapy). These abnormalities generally consist of partial or complete chromosome deletion or addition (del5q, -7, +8, -Y, del20q), whereas balanced or unbalanced translocations are rarely found in MDS. Fluorescence hybridization techniques (fluorescence in situ hybridization [FISH], multiplex FISH, and spectral karyotyping) are useful in detecting chromosomal anomalies in cases in which few mitoses are obtained or rearrangements are complex. Ras mutations are the molecular abnormalities most frequently found in MDS, followed by p15 gene hypermethylation, FLT3 duplications, and p53 mutations, but none of these abnormalities are specific for MDS. The rare cases of balanced translocations in MDS have allowed the identification of genes whose rearrangements appear to play a role in the pathogenesis of some cases of MDS. These genes include MDS1-EVI1 in t(3;3) or t(3;21) translocations, TEL in t(5;12), HIP1 in t(5;7), MLF1 in t(3;5), and MEL1 in t(1;3). Genes more frequently implicated in the pathogenesis of MDS cases, such as those involving del5q, remain unknown, although some candidate genes are currently being studied. Cytogenetic and known molecular abnormalities generally carry a poor prognosis in MDS and can be incorporated into prognostic scoring systems such as the International Prognostic Scoring System.
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PMID:Chromosome and molecular abnormalities in myelodysplastic syndromes. 1150 56

Patients with myelodysplastic syndrome (MDS) show a relatively high incidence of developing cancers. However, it is extremely rare that synchronous double cancers develop in an MDS patient. We report a case of MDS that progressed rapidly into erythroleukemia (M6 by French-American-British classification) complicated by gastric cancer and carcinoma of the papilla of Vater. A 66-year-old man was admitted because of pancytopenia with peripheral blasts. A diagnosis of MDS (with refractory anemia with excess of blasts in transformation [RAEB-T]) was made by bone marrow examination. Chromosome analysis revealed 46,XY. An early gastric cancer was also diagnosed by endoscopic examination. The peripheral blasts gradually proliferated and the disease progressed to M6. A chromosome abnormality 46,XY,del(1)(q42) was detected at the leukemic transformation. A CAG (low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor) regimen was started as a remission-induction therapy. However, obstructive jaundice developed and a marked dilatation of bile ducts was observed by abdominal computed tomography (CT). A carcinoma of the papilla of Vater was detected by endoscopy. As remission was achieved and the pancytopenia improved, the patient subsequently underwent a surgical jejuno-choledochostomy to manage the jaundice. However, the leukemia relapsed thereafter and additional chromosome abnormalities including der(5)t(5;10)(p15:q11) were observed.
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PMID:Myelodysplastic syndrome progresses rapidly into erythroleukemia associated with synchronous double cancers of the stomach and the papilla of Vater. 1153 Aug 7


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