Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: KEGG:D03343 (MDS)
2,225 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report two patients with a myelodysplastic syndrome and the Philadelphia (Ph) chromosome. The first patient was a 73-year-old man who was diagnosed as having a chronic myelomonocytic leukemia in combination with features suggestive of a myeloproliferative syndrome. Chromosomal analysis showed a normal karyotype in the majority of cells, mixed with metaphases containing a standard Ph translocation, t(9;22)(q34;q11), as well as a translocation between chromosome 4 and 6: t(4;6)(p15;p12). Southern blot analysis showed breakpoint cluster region rearrangement as observed in classic chronic myeloid leukemia. The second patient was a 63-year-old man with a myelodysplastic syndrome, type refractory anemia. Cytogenetic study of bone marrow cells at the time of diagnosis revealed a normal karyotype: 46,XY. The initial myelodysplastic syndrome evolved to a myeloproliferative phase with progressive leukocytosis and thrombocytosis. During the terminal phase the Ph chromosome was discovered in 100% of the examined cells. We discuss the correlation between MDS and myeloproliferative diseases, the de novo acquisition of the Ph chromosome during the course of a myelodysplastic syndrome, and review the literature.
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PMID:Cytogenetic and molecular studies of the Philadelphia translocation in myelodysplastic syndromes. Report of two cases and review of the literature. 158 81

Macrocytosis in the elderly is often caused by abnormalities of haematological stem cell differentiation. In this study, a group of elderly patients was analysed for four molecular and cell biological parameters. The aim of the study was to screen elderly patients with idiopathic macrocytic anaemia or MDS for a set of alterations which are related to haematological dysplasia. The analyses used were: DNA-methylation at the calcitonin A gene 5'-area, NRAS point mutations at codons 12 and 13, in vitro colony formation of peripheral blood progenitor cells and cytogenetics of bone marrow cells. The results show that a significant portion of elderly patients with idiopathic macrocytosis have one or more of the abnormalities analysed. Hypermethylation of the calcitonin A gene 5'-area at the chromosome 11 band p15 is relatively common (7/15). Chromosomal aberrations (3/12) and NRAS oncogene point mutations (0/15) were rare findings. In vitro culture of erythroid progenitor cells was relatively frequently abnormal (7/15). Eight of our nine macrocytic patients who did not fulfill the FAB criteria for MDS had at least one of the alterations studied; this suggests that these patients might represent early phases of a stem cell disorder.
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PMID:Idiopathic macrocytic anaemia in the aged: molecular and cytogenetic findings. 766 57

The cytogenetic findings of therapy-related myeloid leukemia (t-ML) in three children are presented. These included one male patient with acute lymphoblastic leukemia (ALL) who underwent bone marrow transplantation and developed therapy-related myeloproliferative disease (t-MPD) in the female-donor hematopoietic cells 2.5 years after receiving radiation and epipodophyllotoxin therapy for ALL testicular relapse. Bone marrow leukemic cell karyotype revealed 46,XX,add (11)(p15) and a normal female karyotype in the peripheral blood lymphocytes. The other two children, one with ALL and one with ganglioneuroblastoma, developed fatal t-MPD and therapy-related acute myeloblastic leukemia (t-AML) preceded by myelodysplastic syndrome (t-MDS), respectively, 5 years after diagnosis, following administration of alkylating agents and irradiation. Monosomy 7 was present in both, and was combined with inv(3)(q21q26) in the second patient. Our review of the cytogenetic findings in 91 previously reported pediatric patients with t-ML suggested that the involvement of 11p15 and 3q21-->23, 3q24-q26 with or without a combination of translocation 11q23 and -7/7q-, respectively, are nonrandom aberrations of t-ML in children. Comparison of the chromosomal changes in t-ML between the pediatric and an adult series revealed some differences which may result from differences in treatment modalities and which, in addition, may indicate a possible role of genetic and/or age-dependent factors in the pathogenesis of therapy-related leukemogenesis in children.
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PMID:Involvement of 11p15 and 3q21q26 in therapy-related myeloid leukemia (t-ML) in children. Case reports and review of the literature. 803 58

A 48-year-old Japanese man was admitted to our hospital because of general fatigue, nasal bleeding, and petechiae on his extremities. He was diagnosed with acute myelomonocytic leukemia with trilineage myelodysplasia (T-MDS). Chromosomal analysis of bone marrow cells revealed t(7;11)(p15;p15), which has been rarely reported but known to be characteristic of Japanese patients. Although t(7;11)(p15;p15) has been reported mainly in acute myelogenous leukemia (AML), it can be occasionally found in so-called stem cell diseases such as chronic myelogenous leukemia or chronic myeloproliferative disorders. Therefore, t(7;11)(p15;p15) might affect trilineage progenitors or stem cells as well as myeloid lineage cells, subsequently resulting in AML with T-MDS, as in our case reported here.
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PMID:t(7;11) and trilineage myelodysplasia in acute myelomonocytic leukemia. 861 92

The NUP98 gene is involved in 3 distinct chromosomal rearrangements, t(7;11)(p15;p15), t(2;11)(q31;p15), and inv(11)(p15q22); all of these NUP98 rearrangements have been identified in the malignant cells of patients with therapy-related acute myelogenous leukemia or myelodysplastic syndrome (t-AML/MDS). Here we report the cloning and characterization of a t(11;20)(p15;q11) translocation from patients with t-MDS. The breakpoint on chromosome 11p15 targets the NUP98 gene and results in the separation of the N-terminal FXFG repeats from the RNA-binding domain located in the C-terminus. The breakpoint on chromosome 20q11 occurs within the gene encoding human DNA topoisomerase I (TOP1). As a result, a chimeric mRNA encoding the NUP98 FXFG repeats fused to the body of DNA topoisomerase I is produced. These results indicate that NUP98 is a recurrent target in therapy-related malignancies, and that TOP1 is a previously unrecognized target for chromosomal translocations.
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PMID:The t(11;20)(p15;q11) chromosomal translocation associated with therapy-related myelodysplastic syndrome results in an NUP98-TOP1 fusion. 1055 15

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

P15INK4B methylation and expression was studied in bone marrow cells obtained from normal individuals, from patients who had been cured of lymphoma, and from patients with either MDS or AML. The level of p15 methylation was very low in normal BM cells and in CD34+ and CD34- subpopulations (0-6.5%; med, = 2.5%). P15INK4B transcripts were present in each of these cell populations. In contrast, methylation was the usual situation in MDS and AML marrows. The presence of methylation of the p15INK4B gene did not always indicate an absence of expression nor was expression always present if methylation was absent. P15INK4B methylation was studied in the marrows of nine patients (one studied twice) who had been cured of lymphoma and in whom hemopoiesis was believed to be normal. Increased methylaton was present in all 10 marrows. These data indicate that p15INK4B methylation is likely to be a very early event in the development of the secondary hematologic disorders.
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PMID:P15INK4B gene methylation and expression in normal, myelodysplastic, and acute myelogenous leukemia cells and in the marrow cells of cured lymphoma patients. 1158 17

Complex chromosomal aberrations (CCAs) can be detected in a substantial proportion of AML and MDS patients, de novo as well as secondary or therapy-related, and are associated with an adverse prognosis. Comprehensive analysis of the chromosomal rearrangements in these complex karyotypes has been hampered by the limitations of conventional cytogenetics. As a result, our knowledge concerning the cytogenetics of these malignancies is sparse. Here we describe a multiplex-FISH (M-FISH) study of CCAs in 36 patients with AML and MDS. M-FISH generated a genome-wide analysis of chromosomal aberrations in CCAs, establishing several cytogenetic subgroups. -5/5q- was demonstrated in the majority of patients (86%). Other rearrangements (present with or without -5/5q-) included: deletion of 7q (47%), 3q rearrangements (19%), and MLL copy gain or amplification (17%). These genetic subgroups seem to display biological heterogeneity: MLL copy gain or amplification in association with 5q- was detected only in AML patients and was significantly associated with extremely short survival (median overall survival: 30 days, P = 0.0102). A partially cryptic t(4;5)(q31;q31), a balanced t(1;8)(p31;q22), and an unbalanced der(7)t(7;14)(q21;q13) were detected as possible new recurrent rearrangements in association with CCAs. Novel reciprocal translocations included t(5;11)(q33;p15)del(5)(q13q31) and t(3;6)(q26;q25). We conclude that AML and MDS with CCAs can be subdivided into molecular cytogenetic subclasses, which could reflect different clinical behavior and prognosis, and that three recurrent chromosomal aberrations are associated with karyotype complexity.
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PMID:Identification of cytogenetic subclasses and recurring chromosomal aberrations in AML and MDS with complex karyotypes using M-FISH. 1174 88

We describe a 55-year-old Japanese woman with therapy-related myelodysplastic syndrome (t-MDS) with 2 independent clones, t(1;2)(p36;p21) and t(11;12)(pl5;ql3). She was diagnosed with acute myeloid leukemia (AML) with cytological features of the bone marrow and peripheral blood. Cytogenetic evaluation revealed a 46,XX karyotype. She received chemotherapy and achieved complete remission (CR). Despite maintenance chemotherapy, she suffered a relapse. Chromosomal analysis showed t(1;2)(p36;p21) in 2 of 20 metaphases. At second CR, this clone transiently disappeared. Nine months later, t(1;2) (p36;p21) was detected again in 3 of 20 metaphases while the patient remained in CR. Six months later, bone marrow examination disclosed trilineage dysplasia without an excess of blasts, suggesting MDS. t(1;2)(p36;p21) was observed in 16 of 20 metaphases. The clinical course and serial cytogenetic findings were diagnostic of t-MDS. The duration of t-MDS was 6 years. During this period, persistent t(1;2)(p36;p21) and transient t(11;12)(p15;q13) were found. When t-MDS evolved toAML, cytogenetic evaluation revealed 46,XX,t(1;2)(p36;p21),del(7)(q22),add(19)(p13).
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PMID:Two independent clones in myelodysplastic syndrome following treatment of acute myeloid leukemia. 1193 66


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