Examination of trisomy 13, 18 and 21 foetal tissues at different gestational ages using FISH.
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In man high levels of aneuploidy are seen in spontaneous abortions. Very few autosomal trisomies survive to birth, the three most common being those for chromosome 13, 18 and 21 giving rise to the syndromes named Patau, Edwards and Down respectively. Since the majority of these spontaneously abort, what makes the survivors different from the aborters? Could it be that they have tissue specific mosaicism with the additional normal cell line supporting survival? In this study fluorescence in situ hybridisation was used as a convenient way to detect trisomy in interphase cells. To study the level of mosaicism across gestation, different tissues from 21 trisomic foetuses were analysed using probes for chromosome 13, 18, 21, X and Y. Two trisomy 18 foetuses exhibited mosaicism. Two others, one trisomy 13 and one trisomy 18 had mosaic placentas. There was no clear association between the limited mosaicism seen and severity of the phenotype. We conclude that at least for this sample set, tissue-specific mosaicism was not likely to be responsible for potential survival to birth. (+info)
A novel syndrome of radiation-associated acute myeloid leukemia involving AML1 gene translocations.
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AML1 is a transcriptional activator that is essential for normal hematopoietic development. It is the most frequent target for translocations in acute leukemia. We recently identified 3 patients in whom pancytopenia developed almost 50 years after high-level radiation exposure from nuclear explosions during or after World War II. In all 3 patients, acute myeloid leukemia (AML) eventually developed that had similar characteristics and clinical courses. Cytogenetics from the 3 patients revealed a t(1;21)(p36;q22), a t(18;21)(q21;q22), and a t(19;21)(q13.4;q22). By fluorescent in situ hybridization (FISH), all 3 translocations disrupted the AML1 gene. Two of these AML1 translocations, the t(18;21) and the t(19;21), have not been reported previously. It is possible that the AML1 gene is a target for radiation-induced AML. (Blood. 2000;95:4011-4013) (+info)
AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation.
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Leukemia-specific AML1/ETO transcripts are detectable in most patients with t(8;21) acute myelogenous leukemia (AML) in long-term remission. To understand the inconsistency between the clinical cure and the presence of "residual disease" at a molecular level, we separated and identified the cells expressing AML1/ETO by phenotype and function. Here we demonstrate that AML1/ETO transcripts are present in a fraction of stem cells, monocytes, and B cells in remission marrow, and in a fraction of B cells in leukemic marrow, but not in T cells. AML1/ETO transcripts also were demonstrated in a fraction of colony-forming cells of erythroid, granulocyte-macrophage, and/or megakaryocyte lineages in both leukemic and remission marrow. These data strongly suggest that the acquisition of the t(8;21) occurs at the level of stem cells capable of differentiating into B cells as well as all myeloid lineages, and that a fraction of the AML1/ETO-expressing stem cells undergo additional oncogenic event(s) that ultimately leads to transformation into AML. (+info)
Newly identified repeat sequences, derived from human chromosome 21qter, are also localized in the subtelomeric region of particular chromosomes and 2q13, and are conserved in the chimpanzee genome.
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Subtelomeric regions have been a target of structural and functional studies of human chromosomes. Markers having a defined structure are especially useful to such studies. Here, we report 93 bp tandem repeat sequences found in the subtelomeric region of human chromosome 21q. They were also detected in the telomeric region of several other chromosomes. Interestingly, the repeat was also found in the 2q13 region which is known to be a position of chromosomal fusion, a major difference between the human and chimpanzee karyotypes. To the best of our knowledge, this repetitive sequence is a new member of human subtelomeric interspersed repeats. (+info)
Analysis of genes under the downstream control of the t(8;21) fusion protein AML1-MTG8: overexpression of the TIS11b (ERF-1, cMG1) gene induces myeloid cell proliferation in response to G-CSF.
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The AML1-MTG8 fusion transcription factor generated by t(8;21) translocation is thought to dysregulate genes that are crucial for normal differentiation and proliferation of hematopoietic progenitors to cause acute myelogenous leukemia (AML). Although AML1-MTG8 has been shown to repress the transcription of AML1 targets, none of the known targets of AML1 are probably responsible for AML1-MTG8-mediated leukemogenesis. In this study, 24 genes under the downstream control of AML1-MTG8 were isolated by using a differential display technique. Analysis with deletion mutants of AML1-MTG8 demonstrated that the regulation of the majority of these genes requires the region of 51 residues (488-538) containing the Nervy homology region 2 (NHR2), through which AML1-MTG8 interacts with MTGR1. Among the 24 genes identified, 10 were considered to be genes under the control of AML1, because their expression was altered by AML1b or AML1a or both. However, the other 14 genes were not affected by either AML1b or AML1a, suggesting the possibility that AML1-MTG8 regulates a number of specific target genes that are not normally regulated by AML1. Furthermore, an up-regulated gene, TIS11b (ERF-1, cMG1), was highly expressed in t(8;21) leukemic cells, and the overexpression of TIS11b induced myeloid cell proliferation in response to granulocyte colony-stimulating factor. These results suggest that the high-level expression of TIS11b contributes to AML1-MTG8-mediated leukemogenesis. (Blood. 2000;96:655-663) (+info)
A novel gene, DSCR5, from the distal Down syndrome critical region on chromosome 21q22.2.
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Based on a detailed sequence of the distal Down syndrome critical region (DSCR), we predicted and molecularly cloned a novel gene, designated DSCR5. We determined the sequences of expressed sequence tags (ESTs) that almost matched the predicted cDNA sequence of DSCR5. Northern blot analysis showed that DSCR5 is expressed in several tissues including the liver, skeletal muscle, heart, pancreas and testis. To determine the 5'-end of DSCR5, the oligo-capping method was employed. Combining the EST sequence data and that from the oligo-capping experiments, we obtained the full-length cDNA sequence of DSCR5. DSCR5 had at least four types of alternatively spliced variants. According to the number of exons, they could be classified into two subtypes: DSCR5alpha and DSCR5beta. DSCR5alpha includes three splice variant subtypes, DSCR5alpha1, alpha2 and alpha3, which each has different first non-coding exon. In addition, the most abundantly isolated form, DSCR5alpha1, shows microheterogeneity of the mRNA start site. Comparison of the sequences between the predicted cDNA and the molecularly cloned cDNA revealed that the computer programs had limited validity to correctly predict the terminal exons. Thus, molecular cloning should always be required to complement the inadequacy of the computer predictions. (+info)
TEL/AML1 gene fusion is related to in vitro drug sensitivity for L-asparaginase in childhood acute lymphoblastic leukemia.
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The t(12;21) translocation resulting in TEL/AML1 gene fusion is present in approximately 25% of patients with precursor B-lineage pediatric acute lymphoblastic leukemia (ALL). Studies suggest an association with a good prognosis; however, relapse can occur. We studied the relation between t(12;21), determined by fluorescence in situ hybridization or polymerase chain reaction, and in vitro drug resistance, measured by the MTT assay, in childhood B-lineage ALL at diagnosis. A total of 180 ALL samples were tested, 51 (28%) of which were positive for t(12;21). The median LC(50) values did not differ significantly between TEL/AML1-positive and -negative samples for prednisolone, dexamethasone, daunorubicin, thiopurines, epipodophyllotoxins, and 4-HOO-ifosfamide. However, the TEL/AML1-positive patients were relatively more sensitive to L-asparaginase (ASP; 5.9-fold; P =.029) and slightly but significantly more resistant to vincristine (1.5-fold; P =.011) and cytarabine (1.5-fold; P =.014). After matching for unevenly distributed patient characteristics-that is, excluding patients younger than 12 months, patients with CD10-negative immature B-lineage ALL, patients with Philadelphia chromosome, and patients who were hyperdiploid (more than 50 chromosomes) from the TEL/AML1 negative group-the only remaining difference was a relative sensitivity for ASP in the TEL/AML1-positive samples (10.8-fold; P =. 012). In conclusion, the presence of TEL/AML1 gene fusion in childhood precursor B-lineage ALL does not seem to be associated with a high in vitro drug sensitivity, except for ASP, indicating that these patients could benefit from treatment schedules with significant use of this drug. (+info)
Collagen XVIII, containing an endogenous inhibitor of angiogenesis and tumor growth, plays a critical role in the maintenance of retinal structure and in neural tube closure (Knobloch syndrome).
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Knobloch syndrome (KS) is an autosomal recessive disorder defined by the occurrence of high myopia, vitreoretinal degeneration with retinal detachment, macular abnormalities and occipital encephalocele. The KS causative gene had been assigned to a 4.3 cM interval at 21q22.3 by linkage analysis of a large consanguineous Brazilian family. We reconstructed the haplotypes of this family with ten additional markers (five were novel) and narrowed the candidate interval to a region of <245 kb, which contains 24 expressed sequence tags, the KIAA0958 gene and the 5' end of the COL18A1 gene. We identified a homozygous mutation at the AG consensus acceptor splice site of COL18A1 intron 1 exclusively among the 12 KS patients, which was not found among 140 control chromosomes. This mutation predicts the creation of a stop codon in exon 4 and therefore the truncation of the alpha1(XVIII) collagen short form, which was expressed in human adult retina. These findings provide evidence that KS is caused by mutations in COL18A1 which, therefore, has a major role in determining the retinal structure as well as in the closure of the neural tube. Therefore, we show for the first time that the absence of a collagen isoform impairs embryonic cell proliferation and/or migration as a primary or secondary effect. (+info)