NUP98 is fused to PMX1 homeobox gene in human acute myelogenous leukemia with chromosome translocation t(1;11)(q23;p15).
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The nucleoporin gene NUP98 was found fused to the HOXA9, HOXD13, or DDX10 genes in human acute myelogenous leukemia (AML) with chromosome translocations t(7;11)(p15;p15), t(2;11)(q35;p15), or inv(11)(p15;q22), respectively. We report here the fusion between the NUP98 gene and another homeobox gene PMX1 in a case of human AML with a t(1;11)(q23;p15) translocation. The chimeric NUP98-PMX1 transcript was detected; however, there was no reciprocal PMX1-NUP98 fusion transcript. Like the NUP98-HOXA9 fusion, NUP98 and PMX1 were fused in frame and the N-terminal GLFG-rich docking region of the NUP98 and the PMX1 homeodomain were conserved in the NUP98-PMX1 fusion, suggesting that PMX1 homeodomain expression is upregulated and that the fusion protein may act as an oncogenic transcription factor. The fusion to NUP98 results in the addition of the strong transcriptional activation domain located in the N-terminal region of NUP98 to PMX1. These findings suggest that constitutive expression and alteration of the transcriptional activity of the PMX1 homeodomain protein may be critical for myeloid leukemogenesis. (+info)
Somatic ATM mutations indicate a pathogenic role of ATM in B-cell chronic lymphocytic leukemia.
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Deletion in chromosome bands 11q22-q23 is one of the most common chromosome aberrations in B-cell chronic lymphocytic leukemia (B-CLL). It is associated with extensive lymph node involvement and poor survival. The minimal consensus deletion comprises a segment, which contains the ATM gene presenting an interesting candidate gene, as mutations in ATM predispose A-T patients to lymphoid malignancies. To investigate a potential pathogenic role of ATM in B-cell tumorigenesis, we performed mutation analysis of ATM in 29 malignant lymphomas of B-cell origin (B-CLL = 27; mantle cell lymphoma, [MCL] = 2). Twenty-three of these carried an 11q22-q23 deletion. In five B-CLLs and one MCL with deletion of one ATM allele, a point mutation in the remaining allele was detected, which resulted in aberrant transcript splicing, alteration, or truncation of the protein. In addition, mutation analysis identified point mutations in three cases without 11q deletion: two B-CLLs with one altered allele and one MCL with both alleles mutated. In four cases analyzed, the ATM alterations were not present in the germ line indicating a somatic origin of the mutations. Our study demonstrates somatic disruption of both alleles of the ATM gene by deletion or point mutation and thus its pathogenic role in sporadic B-cell lineage tumors. (+info)
A new recurrent translocation, t(5;11)(q35;p15.5), associated with del(5q) in childhood acute myeloid leukemia. The UK Cancer Cytogenetics Group (UKCCG)
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Partial deletion of the long arm of chromosome 5, del(5q), is the cytogenetic hallmark of the 5q-syndrome, a distinct subtype of myelodysplastic syndrome-refractory anemia (MDS-RA). Deletions of 5q also occur in the full spectrum of other de novo and therapy-related MDS and acute myeloid leukemia (AML) types, most often in association with other chromosome abnormalities. However, the loss of genetic material from 5q is believed to be of primary importance in the pathogenesis of all del(5q) disorders. In the present study, we performed fluorescence in situ hybridization (FISH) studies using a chromosome 5-specific whole chromosome painting probe and a 5q subtelomeric probe to determine the incidence of cryptic translocations. We studied archival fixed chromosome suspensions from 36 patients with myeloid disorders (predominantly MDS and AML) and del(5q) as the sole abnormality. In 3 AML patients studied, this identified a translocation of 5q subtelomeric sequences from the del(5q) to the short arm of an apparently normal chromosome 11. FISH with chromosome 11-specific subtelomeric probes confirmed the presence of 11p on the shortened 5q. Further FISH mapping confirmed that the 5q and 11p translocation breakpoints were the same in all 3 cases, between the nucleophosmin (NPM1) and fms-related tyrosine kinase 4 (FLT4) genes on 5q35 and the Harvey ras-1-related gene complex (HRC) and the radixin pseudogene (RDPX1) on 11p15.5. Importantly, all 3 patients with the cryptic t(5;11) were children: a total of 3 of 4 AML children studied. Two were classified as AML-M2 and the third was classified as M4. All 3 responded poorly to treatment and had short survival times, ranging from 10 to 18 months. Although del(5q) is rare in childhood AML, this study indicates that, within this subgroup, the incidence of cryptic t(5;11) may be high. It is significant that none of the 24 MDS patients studied, including 11 confirmed as having 5q-syndrome, had the translocation. Therefore, this appears to be a new nonrandom chromosomal translocation, specifically associated with childhood AML with a differentiated blast cell phenotype and the presence of a del(5q). (+info)
Secondary chromosome changes in mantle cell lymphoma.
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BACKGROUND AND OBJECTIVE: Mantle cell lymphomas (MCLs) comprise a rare but distinct clinicopathological entity usually associated with t(11;14). This translocation is regarded as a primary event, but it has been suggested that other as yet unidentified genetic alterations are required for development and progression of MCL. DESIGN AND METHODS: In order to identify recurrent secondary changes that might point towards specific chromosomal regions contributing to the pathogenesis of MCL we studied 43 MCL cases in which clonal chromosomal abnormalities have been found during cytogenetic analysis. RESULTS: In this series 83% of cases were characterized by t(11;14) and in the majority of them the t(11;14) was associated with multiple other chromosomal aberrations. Recurrent secondary changes were found in which imbalances of genetic material prevailed, losses being more common than gains. The former involved thirteen chromosomes, especially 13, 6q, 9q, 11q, 8/8p, 10/10p, and 14, whereas recurrent gains affected 3/3q. Non-randomly occurring breakpoints were relatively infrequent. The identified anomalies were also involved in aberrations observed in the group of MCL not associated with t(11;14). Some of them are shared with other B-cell proliferations. INTERPRETATION AND CONCLUSIONS: The data presented here indicate that MCL is characterized by consistently occurring secondary chromosome changes. Their significance for the development and/or progression of MCL needs to be elucidated and confirmed by further investigations. (+info)
Rapid isolation of chromosomal breakpoints from patients with t(4;11) acute lymphoblastic leukemia: implications for basic and clinical research.
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Chromosomal translocations t(4;11)(q21;q23) are associated with a group of acute lymphoblastic leukemias with very poor prognosis. From the complete sequences of the breakpoint cluster regions of the human MLL and AF-4 translocation partner genes, a novel set of 66 oligonucleotides that facilitates the rapid identification of translocation breakpoints by PCR analysis of genomic DNA was designed. For each breakpoint, a pair of optimally snited primers can be assigned, which improves the monitoring of the disease during treatment. Comparison of the breakpoints with the corresponding parental sequences also contributes to our better understanding of the illegitimate recombination events leading to these translocations. (+info)
A genome scan for familial combined hyperlipidemia reveals evidence of linkage with a locus on chromosome 11.
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Familial combined hyperlipidemia (FCHL) is a common familial lipid disorder characterized by a variable pattern of elevated levels of plasma cholesterol and/or triglycerides. It is present in 10%-20% of patients with premature coronary heart disease. The genetic etiology of the disease, including the number of genes involved and the magnitude of their effects, is unknown. Using a subset of 35 Dutch families ascertained for FCHL, we screened the genome, with a panel of 399 genetic markers, for chromosomal regions linked to genes contributing to FCHL. The results were analyzed by use of parametric-linkage methods in a two-stage study design. Four loci, on chromosomes 2p, 11p, 16q, and 19q, exhibited suggestive evidence for linkage with FCHL (LOD scores of 1.3-2.6). Markers within each of these regions were then examined in the original sample and in additional Dutch families with FCHL. The locus on chromosome 2 failed to show evidence for linkage, and the loci on chromosome 16q and 19q yielded only equivocal or suggestive evidence for linkage. However, one locus, near marker D11S1324 on the short arm of human chromosome 11, continued to show evidence for linkage with FCHL, in the second stage of this design. This region does not contain any strong candidate genes. These results provide evidence for a candidate chromosomal region for FCHL and support the concept that FCHL is complex and heterogeneous. (+info)
Applications of comparative genomic hybridisation in constitutional chromosome studies.
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G band cytogenetic analysis often leads to the discovery of unbalanced karyotypes that require further characterisation by molecular cytogenetic studies. In particular, G band analysis usually does not show the chromosomal origin of small marker chromosomes or of a small amount of extra material detected on otherwise normal chromosomes. Comparative genomic hybridisation (CGH) is one of several molecular approaches that can be applied to ascertain the origin of extra chromosomal material. CGH is also capable of detecting loss of material and thus is also applicable to confirming or further characterising subtle deletions. We have used comparative genomic hybridisation to analyse 19 constitutional chromosome abnormalities detected by G band analysis, including seven deletions, five supernumerary marker chromosomes, two interstitial duplications, and five chromosomes presenting with abnormal terminal banding patterns. CGH was successful in elucidating the origin of extra chromosomal material in 10 out of 11 non-mosaic cases, and permitted further characterisation of all of the deletions that could be detected by GTG banding. CGH appears to be a useful adjunct tool for either confirming deletions or defining their breakpoints and for determining the origin of extra chromosomal material, even in cases where abnormalities are judged to be subtle. We discuss internal quality control measures, such as the mismatching of test and reference DNA in order to assess the quality of the competitive hybridisation effect on the X chromosome. (+info)
CDKN1C expression in Beckwith-Wiedemann syndrome patients with allele imbalance.
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In this study, we have examined CDKN1C expression in BWS patients with allele imbalance (AI) affecting the 11p15 region. Two of two informative patients with AI, attributable to mosaic paternal isodisomy, exhibited reduced levels of CDKN1C expression in the liver and kidney, respectively, relative to expression levels in the equivalent tissues in normal controls. Although overall expression was reduced, some expression from the paternally derived CDKN1C allele was evident, consistent with incomplete paternal imprinting of the gene. One patient showed evidence of maternal allele silencing in addition to AI. These findings show for the first time that CDKN1C expression is reduced in BWS patients with AI and suggest that CDKN1C haploinsufficiency contributes to the BWS phenotype in patients with mosaic paternal isodisomies of chromosome 11. (+info)