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)

De novo acute myeloid leukemia with trilineage myelodysplasia (AML/TMDS) is an uncommon form of leukemia characterized by a dyshematopoietic picture accompanying the acute leukemia, a poor response to induction chemotherapy, and a tendency to relapse with pure myelodysplastic syndrome. Cytogenetic information on this entity is scarce, although some cases have been reported to be associated with t(7;11)(p15;p15). A 41-year-old woman who had a history of radiotherapy for breast cancer presented with AML/TMDS and was found to have a unique t(11;12)(p15;q13) abnormality.
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PMID:De novo AML with trilineage myelodysplasia and a novel t(11;12)(p15;q13). 940 80

p15(INK4b) gene is an inhibitor of cyclin-dependent kinase (CDK) 4 and CDK6 whose expression is induced by transforming growth factor (TGF)beta. Recent reports suggest frequent methylation of the p15(INK4b) gene promoter in leukemias, and it has been proposed that this methylation could be necessary for leukemic cells to escape TGF beta regulation. We investigated the methylation status of p15(INK4b) gene in 53 myelodysplastic syndromes (MDS) cases, including nine that had progressed to acute myeloid leukemia (AML), using a recently described sensitive method where polymerase chain reaction (PCR) is preceded by bisulfite modification of DNA (methylation specific PCR). p15(INK4b) methylation was observed in 20 of 53 (38%) of the cases. Twenty of the 24 patients with greater than 10% bone marrow blasts had p15(INK4b) methylation (including all nine patients who had progressed to AML) as compared with none of MDS patients with <10% bone marrow blasts. No correlation between karyotypic abnormalities and methylation status was found. Patients with p15(INK4b) methylation had a worse prognosis, but the prognostic significance of p15(INK4b) methylation was no more found by multivariate analysis, due to its strong correlation to the percentage of marrow blasts. In 10 MDS cases, sequential DNA samples were available. In five of them, methylation of the p15(INK4b) gene was detected at leukemic transformation, but not at diagnosis. Our results showed that methylation of the p15(INK4b) gene in MDS is correlated with blastic bone marrow involvement and increases with disease evolution toward AML. It suggests that proliferation of leukemic cells might require an escape of regulation of the G1 phase of the cell cycle, and possibly of TGF beta inhibitory effect.
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PMID:Methylation of the p15(INK4b) gene in myelodysplastic syndromes is frequent and acquired during disease progression. 953 10

The cyclin-dependent kinase inhibitors known as p15, p16, p18 and p19 have been suggested as candidates for tumor suppressor genes. The main genetic alterations are deletions (bi- or monoallelic) or 5' CpG island methylation of p15 and p16; very few cases or cell lines had p18 or p19 deletions or hypermethylation. Hypermethylation and homozygous deletions of tumor suppressor genes establish a new paradigm of inactivation by lack of expression, in contrast to the previously identified tumor suppressors which are predominantly inactivated by point mutations followed by loss of the wild-type allele. Here, the literature data on alterations of this gene family in more than 4700 primary cases of leukemia or lymphoma and some 320 continuous leukemia-lymphoma cell lines are summarized. Among hematopoietic malignancies, the highest frequencies of p15del and p16del were seen in acute lymphoblastic leukemia (ALL) (>30%) with striking rates in T-ALL (>50%), but also high rates in B cell precursor (BCP)-ALL (>20%); the rates of deletions in chronic lymphoid leukemia (CLL), multiple myeloma, acute and chronic myeloid leukemia (AML and CML), and myelodysplastic syndromes (MDS) were rather low, only some B cell and T cell lymphomas showed increased frequencies. Results are quite different with regard to the second mode of inactivation, hypermethylation of the promoter region. Here, p15 is most often inactivated, at particularly high frequencies in the disorders lacking any p15/p16 deletions: 40-80% p15met in AML, MDS and multiple myeloma. Also p15met rates in BCP- and T-ALL cases were high (c. 40%). There is controversy concerning the prognostic impact of p15 and p16 aberrations with some studies describing a significant correlation between inactivation of these genes and poor prognosis, while most others did not detect any prognostic relevance, at least in pediatric ALL; there may be a worse prognosis for adults with B or T cell lymphomas. Despite the small number of cases studied, paired sequential analyses suggested that disease progression is associated with loss of p15/p16 activity in a certain percentage of adult patients. p15del/p16del and p15met/p16met were also detected in the large panel of leukemia-lymphoma cell lines studied. In general, the results in cell lines reproduce the data seen in primary cells with the important difference that the rates of p15/p16 inactivation are clearly higher in the cultured cells compared with the freshly explanted cells. Retrovirus- or electroporation-mediated ectopic gene transfer of p16 wild-type into p16-deficient cell lines led to growth inhibition, arrest in G1 (without apoptosis) and occasionally to differentiation, suggesting that the malignant phenotype of p16-/- cell lines can, at least partially, be reversed by restoring p16 gene expression. A striking inverse correlation between the absence of p16 (due to deletion) and presence of wild-type retinoblastoma gene was observed in cell lines confirming a common growth suppressor pathway; no comparable relationship of p16 inactivation with p53 was detected. Paired analysis of cell lines and corresponding primary cell material showed that in all instances tested both populations carried the same gene configuration of p15 and p16. Thus, p15del or p16del did not occur during establishment of the cell lines or during prolonged culture. It is likely that p15 or p16 deletions already acquired in vivo provide a dramatic growth advantage for the immortalization process in vitro, thus increasing the success rate for cell line establishment which is commonly extremely difficult. In conclusion, the present review suggests an involvement of the p15 and p16 tumor suppressor genes in leukemo- and lymphomagenesis. Future studies will determine their exact role in the development and progression of hematopoietic neoplasms. These genes may represent interesting targets for new therapeutic strategies.
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PMID:Review of alterations of the cyclin-dependent kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human leukemia-lymphoma cells. 963 10

The haematological diversity of myelodysplastic syndromes (MDS) mandates that therapeutic strategies for this disease be guided by an understanding of the disease biology. Insights into the pathobiology of this disease have given rise to novel treatment strategies which exploit basic biological disturbances. Myelodysplastic bone marrow progenitors from patients with low leukaemia burden display an accelerated senescence phenotype which is characterised by impaired response to trophic signals and premature apoptotic death of primitive haematopoietic progenitors. Elaboration of aptogenic cytokines such as TNF-alpha and IL-1beta may reinforce this sequence by up-regulating cellular expression of fas ligand and its cognate receptor, suppressing responsiveness to growth factor stimulation, and accelerating apoptotic cell death. Inactivation of p15 or other tumour suppressor genes antedate disease progression and the emergence of blast populations with reduced capacity for fas mediated cell death. Herein we review the current understanding of the pathobiology of MDS and promising strategies for therapeutic intervention.
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PMID:Pharmacological differentiation and anti-apoptotic therapy in myelodysplastic syndromes. 1010 Dec 9

In a survey of childhood therapy-related acute myeloid leukemia/myelodysplastic syndrome (t-AML/MDS) in Japan, we found 11p15 translocations in 5 (6%) of 81 children with t-AML/MDS. t(11;17)(p15;q21), t(11;12)(p15;q13), t(7;11)(p15;p15), inv(11)(p15q22), and add(11)(p15) were each found in one patient. Southern blotting and/or RT-PCR analyses revealed rearrangements of the NUP98 gene in tumor samples of all five patients. Rearrangements of DDX10 were detected in t-AML/MDS cells with inv(11), and rearrangements of HOXA9 were detected in t-AML cells with t(7;11). The 17q21 breakpoint of t(11;17) and the 12q13 breakpoint of t(11;12)(p15;q13) coincided with the loci of the HOXB and HOXC gene families, respectively. Therefore, it is reasonable to speculate that one of the HOXB genes and one of the HOXC genes were fused to NUP98 by t(11;17) and t(11;12), respectively, in t-AML/MDS cells. We propose that NUP98 may be a target gene for t-AML/MDS, and that t-AML/MDS with a fusion of NUP98 and HOX or DDX10 genes may be more frequent in children than in patients of other age groups.
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PMID:11p15 translocations involving the NUP98 gene in childhood therapy-related acute myeloid leukemia/myelodysplastic syndrome. 1050 19

Cytogenetic studies were performed in 140 patients with myelodysplastic syndrome (MDS) at diagnosis. Chromosome 11 anomalies were found in 7 cases (5%); 2 of these patients had refractory anemia (RA), 2 had refractory anemia with excess of blasts (RAEB), 1 had RAEB in transformation (RAEB-t), and 2 had chronic myelomonocytic leukemia (CMMoL) according to the French-American-British (FAB) Cooperative Group criteria. The chromosome 11 abnormalities comprised trisomy 11 (2 patients), monosomy 11 (1 patient), del(11)(q23) (2 patients), add(11)(p15) (1 patient), and der(11) t(3;11)(p21;q23) (1 patient). Abnormalities involving band q23 of chromosome 11 occurred in 3 cases and were the most common alteration. However, specific chromosomal alterations were not associated with any FAB classification group. These findings and their implications in the biology of MDS are discussed.
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PMID:Chromosome 11 abnormalities in myelodysplastic syndromes. 1052 36

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

The reciprocal translocation t(7;11)(p15;p15) has been reported as occurring mainly in acute myelogenous leukaemia (AML) and the acute phase of chronic myelogenous leukaemia (CML). This translocation in AML involves both the nucleoporin gene NUP98 on 11p15 and the homeobox gene HOXA9 on 7p15. The invariant chimaeric NUP98/HOXA9 transcripts are a result of the fact that each breakpoint of the NUP98 and the corresponding breakpoint of the HOXA9 gene cluster occur within the same intron. Only one patient with myelodysplastic syndromes (MDS) carrying this chromosome aberration has been reported, but this study did not involve molecular analysis. We describe two patients with MDS associated with t(7;11): patient 1 was a Japanese man diagnosed with chronic myelomonocytic leukaemia; patient 2 was a Japanese woman with refractory anaemia with excess of blasts in transformation. Within a year both patients developed AML and showed multidrug resistance to chemotherapy. Southern blot analysis showed rearrangements of the NUP98 gene of the two patients and the HOXA9 gene of patient 2. Patient 1 had two types of the novel NUP98/HOXA9 fusion transcripts. Each of them lacked the common 141 bp NUP98 exon which was contained in the NUP98/HOXA9 fusion transcripts detected in patient 2 and the reported AML cases. These data indicated that t(7;11) could determine the development of various myeloid leukaemias and that the resultant chimaeric transcripts are heterogenous.
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PMID:Molecular heterogeneity of the NUP98/HOXA9 fusion transcript in myelodysplastic syndromes associated with t(7;11)(p15;p15). 1058 65

The myelodysplastic syndromes (MDS) are clonal myeloid disorders characterized by bone marrow cell dysplasia and ineffective hematopoiesis leading to peripheral refractory cytopenias. The course of the disease ranges from a chronic status with progressively impaired hematopoiesis to rapid evolution to acute myeloid leukemia (AML). A panel of continuous malignant hematopoietic cell lines has been established from the whole spectrum of MDS variants and also from the different stages of the diseases, namely from the MDS phase or the overt leukemia post-MDS phase. Ten cell lines were derived from the various MDS subtypes; 17 cell lines were established from patients with leukemia (mainly AML) post-MDS. While most cell lines display myelocytic, monocytic or erythroid features, some cell lines carry lymphoid characteristics (precursor B-cell, B-cell, or T-cell), With regard to these lymphoid MDS-derived cell lines, more detailed authentication (prove of derivation from the assumed patient) and verification (prove of the malignant nature of the cell line and derivation from the assumed neoplastic cells) are required to validate the cell lines as true in vitro representatives of MDS and to exclude any cross-contamination with other cells or immortalization of normal bystander cells. On the other hand, lymphoid MDS-derived cell lines may attest to the clonal nature of MDS which may afflict progenitor cells giving rise to lymphoid or myelomonocytoid cells. Many of the MDS-derived cell lines carry cytogenetic and molecular genetic abnormalities typically associated with MDS: gain or loss of all or parts of chromosomes 5, 7, 8 and 20 (-5/5q-, -7/7q-, + 8, 20q-); alterations of oncogenes and tumor suppressor genes (IRF-1, p15, p16, p53, RAS, RB). In summary, the present panel of cell lines provides continuously growing cells and thus unlimited cell material for use as in vitro paradigms covering the whole spectrum of MDS-related hematopoetic malignancies. Properly authenticated and verified MDS-derived cell lines which should be made freely available will represent important research tools for the study of MDS biology.
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PMID:Malignant hematopoietic cell lines: in vitro models for the study of myelodysplastic syndromes. 1065 45

We reported on 2 atomic bomb survivors(a 60-year-old man and 63-year-old woman)suffering myelodysplastic syndrome(MDS) associated with 1p32 chromosomal abnormalities. They were exposed to atomic bomb radiation at distances of 1.2 and 1.1 km, respectively, and were given a diagnosis of MDS 44 and 46 years after the bombing, respectively. The male patient had refractory anemia(RA) and a bone marrow cell karyotype of 46, XY, del(1)(p22p32), t(8;11)(p11;p15). The female patient had RA with excess of blasts (RAEB) and a karyotype of 45, X, -X, t(1;11)(p32;q23), +del(1)(p32), inv(3) (p21q27), del(5)(q15), -6, -9, -19, +mar 1, +mar 2. Multi-separated nuclear megakaryocytes were observed in both patients. These findings suggested that they had been exposed to radiation near the atomic explosion despite the fact that their symptoms of MDS developed more than 40 years after the bombing. 1p32 is known to be the locus of the TAL1 gene. However, Southern blot analysis did not reveal rearrangement of the TAL1 gene in the male patient.
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PMID:[Chromosome 1 abnormalities at band 1p32 in two atomic bomb survivors with myelodysplastic syndrome]. 1072 46

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