| 1. |
- Panagopoulos, Ioannis, et al.
(författare)
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Expression of NUP98/TOP1, but not of TOP1/NUP98, in a treatment-related myelodysplastic syndrome with t(10;20;11)(q24;q11;p15).
- 2002
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 34:2, s. 249-254
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Tidskriftsartikel (refereegranskat)abstract
- The t(11;20)(p15;q11) is a rare but recurrent translocation that so far has been described in only four acute myeloid leukemias (AMLs), two treatment-related myelodysplastic syndromes (t-MDSs), and one case of polycythemia vera. Recently, the t(11;20) was shown to result in a fusion of the NUP98 and TOP1 genes, with expression of the NUP98/TOP1 chimera encoded by the der(11)t(11;20), but not of the reciprocal TOP1/NUP98 on the der(20)t(11;20). The genomic breakpoints were subsequently mapped to introns 13 and 7 of NUP98 and TOP1, respectively. We present here a t-MDS with a three-way variant translocation, t(10;20;11)(q24;q11;p15), that generates a der(11)t(11;20) but not a der(20)t(11;20), strongly suggesting that the der(11) harbors the critical genetic rearrangement. Reverse transcriptase-polymerase chain reaction (RT-PCR) revealed a NUP98/TOP1 fusion in which exon 13 of NUP98 was fused in-frame with exon 8 of TOP1. Extra long (XL) genomic PCR and subsequent sequence analyses showed that the breakpoint in NUP98 occurred at nucleotide (nt) 3461 of intron 13, close to a MER (medium reiteration frequency interspersed repetitive element) repeat, and that the breakpoint in TOP1 was at nt 1436 of intron 7, downstream of a MIR (mammalian-wide interspersed repeats) repetitive element. Genomic XL PCR did not amplify the reciprocal TOP1/NUP98, nor was this chimera expressed, as expected from the cytogenetic finding. The present results provide further support for the involvement of the NUP98/TOP1 transcript, but not of the reciprocal one, in the development of MDS/AML. Furthermore, the three cases genomically characterized to date have all been treatment-related and have all harbored breakpoints in intron 13 of NUP98 and intron 7 of TOP1, suggesting that these introns are susceptible to chemotherapy-induced breakage.
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| 2. |
- Möller, Emely, et al.
(författare)
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POU5F1, encoding a key regulator of stem cell pluripotency, is fused to EWSR1 in hidradenoma of the skin and mucoepidermoid carcinoma of the salivary glands
- 2008
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Ingår i: Journal of Pathology. - : Wiley. - 1096-9896 .- 0022-3417. ; 215:1, s. 78-86
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Tidskriftsartikel (refereegranskat)abstract
- The EWSR1 gene is known to play a crucial role in the development of a number of different bone and soft tissue tumours, notably Ewing's sarcoma. POU5F1 is expressed during early development to maintain the totipotent status of embryonic stem and germ cells. In the present study, we report the fusion of EWSR1 and POU5F1 in two types of epithelial tumours: hidradenoma of the skin and mucoepidermoid carcinoma of the salivary glands. This finding not only broadens considerably the spectrum of neoplasms associated with EWSR1 fusion genes but also strengthens the evidence for shared pathogenetic mechanisms in the development of adnexal and salivary gland tumours. Reminiscent of the previously reported fusion genes involving EWSR1, the identified transcript is predicted to encode a chimeric protein consisting of the EWSR1 amino-terminal domain and the POU5F1 carboxy-terminal domain. We assessed the transcriptional activation potential of the chimera compared to the wild-type proteins, as well as activation of transcription through the oct/sox composite element known to bind POU5F1. Among other POU5F1 target genes, this element is present in the promoter of NANOG and in the distal enhancer of POU5F1 itself. Our results show that although the chimera is capable of significant transcriptional activation, it may in fact convey a negative regulatory effect on target genes.
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| 3. |
- Hallor, Karolin Hansén, et al.
(författare)
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Fusion of the EWSR1 and ATF1 genes without expression of the MITF-M transcript in angiomatoid fibrous histiocytoma
- 2005
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 44:1, s. 97-102
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Tidskriftsartikel (refereegranskat)abstract
- Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumor that usually occurs in children and young adults. Only two cases of AFH with genetic rearrangements have been reported previously; both of these had a FUS-ATF1 fusion gene. We have studied an AFH from a 9-year-old boy whose tumor displayed a t(12;22)(q13;q12) as the sole cytogenetic aberration. FISH,RT-PCR, and sequence analyses revealed an EWSR1-ATF1 fusion gene that has previously been reported in clear cell sarcoma (CCS), a soft tissue sarcoma that is morphologically and clinically distinct from AFH. This study thus has demonstrated that the EWSR1-ATF1 chimera represents a fusion gene that can be associated with different tumor types. Simultaneous expression of the EWSR1-ATF1 and MITF-M transcripts in CCS has led to the proposal that the MITF-M promoter is transactivated by EWSR1-ATF1. The AFH, however, did not express the MITF-M transcript, supporting the theory that MITF-M expression in CCS is a reflection of its cellular origin, rather than a consequence of the presence of an EWSR1-ATF1 fusion protein. Activation of the EWSR1-ATF1 oncogene is probably an early step in the transformation process, but the overall gene expression patterns are likely to vary considerably between AFH and CCS, in keeping with their clinicopathologic differences.
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| 4. |
- Gebre-Medhin, Samuel, et al.
(författare)
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Telomeric associations correlate with telomere length reduction and clonal chromosome aberrations in giant cell tumor of bone.
- 2009
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Ingår i: Cytogenetic and Genome Research. - : S. Karger AG. - 1424-859X .- 1424-8581. ; 124:2, s. 121-127
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Tidskriftsartikel (refereegranskat)abstract
- Giant cell tumor of bone (GCTB) is characterized cytogenetically by frequent telomeric associations (tas). To explore the mechanisms behind the formation of tas in GCTB and to investigate their karyotypic consequences, the frequencies of tas and clonal aberrations other than tas in 20 GCTBs were compared to telomere length and status, as assessed by quantitative PCR, fluorescence in situ hybridization (FISH), and expression levels of four genes involved in telomere maintenance. Based on the G-banding results, the tumors were divided into two groups, one with a high frequency of tas and one with a low frequency. Clonal aberrations were found to be restricted to the group with a high level of tas, and the same group showed a significantly larger reduction in telomere length in tumor cells compared to peripheral blood cells. Furthermore, 65 out of 66 tas analyzed by FISH were negative for telomeric sequences. The expression levels of TERT, TERF1, TERF2, and POT1 did not correlate with telomere length or the frequency of tas. Thus, the present findings provide strong support for the notion that decreased telomere length is a prerequisite for tas in GCTBs and that the clonal changes occurring in GCTBs are derived from tas.
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| 5. |
- Panagopoulos, Ioannis, et al.
(författare)
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Fusion of the MORF and CBP genes in acute myeloid leukemia with the t(10,16)(q22,p13)
- 2001
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 10:4, s. 395-404
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Tidskriftsartikel (refereegranskat)abstract
- The CBP gene at 16p 13 fuses to MOZ and MLL as a result of the t(8,16)(p11,p13) in acute (myelo)monocytic leukemias (AML M4/M5) and the t(11,16)(q23,p13) in treatment-related AML, respectively. We show here that a novel t(10,16)(q22,p13) in a childhood AML M5a leads to a MORF-CBP chimera. RT-PCR using MORF forward and CBP reverse primers amplified a MORF-CBP fusion in which nucleotide 3103 of MORF was fused in-frame with nucleotide 284 of CBP. Nested RT-PCR with CBP forward and MORF reverse primers generated a CBP-MORF transcript in which nucleotide 283 of CBP was fused in-frame with nucleotide 3104 of MORF. Genomic analyses revealed that the breaks were close to Alu elements in intron 16 of MORF and intron 2 of CBP and that duplications had occurred near the breakpoints. A database search using MORF cDNA enabled us to construct an exon-intron map of the MORF gene. The MORF-CBP protein retains the zinc fingers, two nuclear localization signals, the histone acetyltransferase (HAT) domain, a portion of the acidic domain of MORF and the CBP protein downstream of codon 29. Thus, the part of CBP encoding the RARA-binding domain, the CREB-binding domain, the three Cys/His-rich regions, the bromodomain, the HAT domain and the Glu-rich domains is present. In the reciprocal CBP-MORF, part of the acidic domain and the C-terminal Ser- and Met-rich regions of MORF are likely to be driven by the CBP promoter. Since both fusion transcripts were present, their exact role in the leukemogenic process remains to be elucidated.
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| 6. |
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| 7. |
- Papazoglou, D., et al.
(författare)
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The Fatty Acid Amide Hydrolase (FAAH) Pro129Thr Polymorphism is not Associated with Severe Obesity in Greek Subjects
- 2008
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Ingår i: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 1439-4286 .- 0018-5043. ; 40:12, s. 907-910
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Tidskriftsartikel (refereegranskat)abstract
- Fatty amid acid hydrolase (FAAH) has been implicated at both protein and gene level with obesity. An association between Pro129Thr variant of the FAAH gene and obesity has been described, but various studies have yielded conflicting results. Our aim was to determine whether this polymorphism is related to severe obesity and whether it confers a risk for variability of quantitative metabolic traits in a cohort of Greek obese Subjects. Two groups of severely obese Subjects (BMI >40 kg/m(2)) were studied: a group of 158 metabolically healthy and a group of 145 obese subjects with metabolic syndrome, which were compared to a Control group consisting of 121 lean individuals. We did not find any association between the Pro129Thr polymorphism with severe obesity in both subgroups of obese subjects, between these two subgroups (p = 0.11) or on basic anthropometric characteristics in the three groups. Statistically significant differences were found for glucose and HDL in metabolically healthy Subjects and HDL in the control group. The borderline significant p-values were not significant after correction for multiple testing. We were unable to find robust evidence of an association of the Pro 129Thr variant with severe obesity, and any related quantitative traits among the obese Greek Subjects examined.
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| 8. |
- Storlazzi, Tiziana, et al.
(författare)
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Fusion of the FUS and BBF2H7 genes in low grade fibromyxoid sarcoma
- 2003
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 12:18, s. 2349-2358
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Tidskriftsartikel (refereegranskat)abstract
- The FUS gene at 16p11 fuses with DDIT3 and ATF1 as the result of translocations with chromosome band 12q13 in myxoid liposarcoma and angiomatoid fibrous histiocytoma, respectively, and with ERG as the result of a t(16;21)(p11;q22) in acute myeloid leukemia. We here show that a t(7;16)(q33;p11) in two cases of low grade fibromyxoid sarcoma fuses the FUS gene to BBF2H7, a previously uncharacterized gene that is homologous to the Drosophila Bbf-2 gene. BBF2H7 spans more than 120 kbp genomic DNA, is composed of 12 exons and contains a 1560 bp open reading frame. It codes for a 519 amino acid protein that contains a basic DNA binding and leucine zipper dimerization (B-ZIP) motif, highly similar to that in the OASIS, CREB-H, CREB4 and CREB3 transcription factors, followed by a hydrophobic region predicted to be an alpha-helical transmembrane domain. Reverse transcription-polymerase chain reaction (RT-PCR), using FUS forward and BBF2H7 reverse primers, amplified FUS/BBF2H7 chimeric transcripts composed of the first five exons and part of exon 6 of FUS and part of exon 5 and exons 6-12 of BBF2H7. The FUS/BBF2H7 chimera codes for a protein containing the N-terminus of FUS and the B-ZIP domain and the C-terminus of BBF2H7.
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| 9. |
- Panagopoulos, Ioannis, et al.
(författare)
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Characterization of the human CREB3L2 gene promoter
- 2009
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Ingår i: Oncology Reports. - : Spandidos Publications. - 1791-2431 .- 1021-335X. ; 21:3, s. 615-624
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Tidskriftsartikel (refereegranskat)abstract
- CREB3L2 encodes a member of the CREB3 family of transcription factors. We characterized its promoter region, showing that it is asymmetrically bidirectional, also driving the expression of a variant of AKR1D1. It has a CRE binding site which is conserved among mammalians; removal or alteration of it resulted in reduced promoter activity. When transiently transfecting the HEK293 cell line with constructs with partially deleted promoter regions, 5' deletions beyond 1058-bp upstream of the transcription starting site resulted in successive reduction of the activity. The inclusion of the untranslated part of CREB3L2 exon 1 strongly inhibited the promoter activity. Forskolin resulted in a decreased reporter activity, whereas phorbol 12-myristate 13-acetate increased the promoter activity irrespective of the status of the CRE binding site. The presence of the CRE site indicates autoregulation of CREB3L2 and/or regulation via other members of the CREB3 family or a variety of bZIP transcription factors.
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| 10. |
- Panagopoulos, Ioannis, et al.
(författare)
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Characterization of the native CREB3L2 transcription factor and the FUS/CREB3L2 chimera
- 2007
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 46:2, s. 181-191
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Tidskriftsartikel (refereegranskat)abstract
- CREB3L2 was first identified as the 3'-partner of FUS in a fusion gene that seems to be specific for low grade fibromyxoid sarcoma. In silico analyses suggest that the predicted CREB3L2 protein is a member of the CREB3 family of transcription factors, with its bZIP domain being highly similar to that in CREB3L1, CREB3L3, CREB3L4, CREB3, and Drosophila Bbf-2. In the present study, the authors assessed various cellular outcomes after transfection of NIH3T3 and HEK-293 cells with constructs containing full-length and truncated versions of CREB3L2 and FUS/CREB3L2. Northern blot of CREB3L2 mRNA revealed a 7.4 kbp band that contains 0.4 kbp and 5.5 kbp untranslated 5' and 3' regions, respectively. CREB3L2 constructs containing the first 120 amino acids (aa) showed the highest transcriptional activation. Much stronger transcriptional activation was consistently seen for the FUS/CREB3L2 constructs than for the corresponding CREB3L2 constructs. Transcriptional activity was achieved through the box-B element, ATF6 and CRE binding sites, as well as the GRP78 promoter. Proteins encoded by full-length CREB3L2 and FUS/CREB3L2 were localized to reticular structures of the cytoplasm, whereas the corresponding, truncated proteins lacking the transmembrane domain and the carboxy-terminal part of CREB3L2 resided within the nucleus. The results of the present study show that CREB3L2 is not only structurally, but also functionally very similar to CREB3L1. Thus, studies regarding the pathways influenced by wild-type CREB3L2 should provide valuable clues to the pathogenetic significance of the FUS/CREB3L2 chimera in low grade fibromyxoid sarcoma.
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