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| 2. |
- Gisselsson Nord, David, et al.
(författare)
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Distinct evolutionary mechanisms for genomic imbalances in high-risk and low-risk neuroblastomas
- 2007
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Ingår i: Journal of Carcinogenesis. - : Medknow. - 0974-6773 .- 1477-3163. ; 6, s. 15-15
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: Neuroblastoma (NB) is the most common extracranial solid tumour of childhood. Several genomic imbalances correlate to prognosis in NB, with structural rearrangements, including gene amplification, in a near-diploid setting typically signifying high-risk tumours and numerical changes in a near-triploid setting signifying low-risk tumours. Little is known about the temporal sequence in which these imbalances occur during the carcinogenic process. METHODS: We have reconstructed the appearance of cytogenetic imbalances in 270 NBs by first grouping tumours and imbalances through principal component analysis and then using the number of imbalances in each tumour as an indicator of evolutionary progression. RESULTS: Tumours clustered in four sub-groups, dominated respectively by (1) gene amplification in double minute chromosomes and few other aberrations, (2) gene amplification and loss of 1p sequences, (3) loss of 1p and other structural aberrations including gain of 17q, and (4) whole-chromosome gains and losses. Temporal analysis showed that the structural changes in groups 1-3 were acquired in a step-wise fashion, with loss of 1p sequences and the emergence of double minute chromosomes as the earliest cytogenetic events. In contrast, the gains and losses of whole chromosomes in group 4 occurred through multiple simultaneous events leading to a near-triploid chromosome number. CONCLUSION: The finding of different temporal patterns for the acquisition of genomic imbalances in high-risk and low-risk NBs lends strong support to the hypothesis that these tumours are biologically diverse entities, evolving through distinct genetic mechanisms.
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| 3. |
- Holm, Caroline, et al.
(författare)
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Cyclin A1 expression and associations with disease characteristics in childhood acute lymphoblastic leukemia
- 2006
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Ingår i: Leukemia research. - : Elsevier. - 0145-2126 .- 1873-5835. ; 30:3, s. 254-261
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Tidskriftsartikel (refereegranskat)abstract
- A critical cell cycle regulatory protein, cyclin A1, has been implicated in the development of acute myeloid leukemia (AML). Here, we have examined the expression and clinical significance of cyclin A1 in childhood acute lymphoblastic leukemia (ALL). Cyclin A1 was highly expressed in lymphoblastic leukemic cell lines and in 22 of 30 ALL patients (73%). Cyclin A1 expression correlated with patient age (P=0.006), but not with cytogenetic abnormalities. Patients with high levels of cyclin A1 had poorer event-free survival (57.9%) compared to patients with lower levels (75%).
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| 4. |
- Koppen, Arjen, et al.
(författare)
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Dickkopf-3 expression is a marker for neuroblastic tumor maturation and is'-down-regulated by MYCN
- 2008
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136. ; 122:7, s. 1455-1464
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Tidskriftsartikel (refereegranskat)abstract
- Neuroblastoma and ganglioneuroma are neuroblastic tumors originating from the developing sympathetic peripheral nervous system. Ganglioneuromas are usually benign, while neuroblastomas have a variable prognosis and include very aggressive tumors. Examples exist of neuroblastomas regressing to ganglioneuromas and ganglioneuromas progressing to neuroblastomas. Little is known of the molecular differences between the tumor types. Here we report that Dickkopf-3 (DKK3), a putative extra cellular inhibitor of the Wnt/beta-catenin pathway, showed a strongly differential expression between neuroblastoma and ganglioneuroma. Microarray analyses of 109 neuroblastic tumors revealed that DKK3 is strongly expressed in ganglioneuroma but only weakly in neuroblastoma. Low DKK3 expression in neuroblastoma correlated with a poor prognosis. The expression of DKK3 in the tumor series and in neuroblastoma cell lines was inversely correlated with the expression of the MYCN oncogene. Analysis of, 2 neuroblastoma cell lines with inducible activity of MYCN showed that DKK3 is down-regulated by MYCN. We subsequently generated cell lines with inducible expression of DKK3, which revealed an inhibitory effect of DKK3 on proliferation. High DKK3 expression in the benign ganglioneuromas and down-regulation of DKK3 by MYCN in neuroblastoma might contribute to the strongly different clinical behavior of both neuroblastic tumor types.
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| 5. |
- Koppen, Arjen, et al.
(författare)
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Direct regulation of the minichromosome maintenance complex by MYCN in neuroblastoma
- 2007
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 43:16, s. 2413-2422
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Tidskriftsartikel (refereegranskat)abstract
- The c-Myc and MYCN oncogenes strongly induce cell proliferation. Although a limited series of cell cycle genes were found to be induced by the myc transcription factors, it is still unclear how they mediate the proliferative phenotype. We therefore analysed a neuroblastoma cell line with inducible MYCN expression. We found that all members of the minichromosome maintenance complex (MCM2 - 7) and MCM8 and MCM10 were up-regulated by MYCN. Expression profiling of 110 neuroblastoma tumours revealed that these genes strongly correlated with MYCN expression in vivo. Extensive chromatin immunoprecipitation experiments were performed to investigate whether the MCM genes were primary MYCN targets. MYCN was bound to the proximal promoters of the MCM2 to -8 genes. These data suggest that MYCN stimulates the expression of not only MCM7, which is a well defined MYCN target gene, but also of the complete minichromosome maintenance complex. (c) 2007 Elsevier Ltd. All rights reserved.
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| 6. |
- Lindberg, Eva, et al.
(författare)
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Concurrent gain of 17q and the MYC oncogene in a medullomyoblastoma
- 2007
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Ingår i: Neuropathology. - : Wiley. - 0919-6544 .- 1440-1789. ; 27:6, s. 556-560
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Tidskriftsartikel (refereegranskat)abstract
- Medullomyoblastoma (MMB) is a rare cerebellar childhood tumor containing both myoblastic and primitive neuroectodermal components. Similar to the scenario in classical medulloblastoma, which contains the primitive neuroectodermal component only, gain of sequences from the long arm of chromosome 17 (17q) and gain of the MYC gene in 8q have been implicated in the pathogenesis of MMB. Because karyotypic analysis has not previously been performed for MMB, the mechanisms behind genomic imbalances in this tumor have remained unknown. Several other central aspects of this tumor, such as histocytogenetic origin, clinical characteristics, tumor behavior and prognosis, also remain unknown. We here report neuropathological and cytogenetic features of an MMB in a 3-year-old boy. Chromosome banding analysis and multicolor karyotyping revealed a hyperdiploid karyotype including an unbalanced 1; 17 translocation and isochromosome 17q formation, both leading to gain of 17q. There were also two extra copies of chromosome 8, leading to gain of the MYC oncogene, trisomies 5 and 13, and monosomy 9. Clonal chromosome changes were present in both the myoblastic and neuroectodermal components. Our findings support the notion that MMB and classical medulloblastoma arise through similar genetic mechanisms and that the two main tissue components in MMB are clonally related.
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| 7. |
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| 8. |
- Paulsson, Kajsa, et al.
(författare)
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Characterisation of genomic translocation breakpoints and identification of an alternative TCF3/PBX1 fusion transcript in t(1;19)(q23;p13)-positive acute lymphoblastic leukaemias.
- 2007
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 138:2, s. 196-201
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Tidskriftsartikel (refereegranskat)abstract
- The t(1;19)(q23; p13), one of the most common translocations in childhoodand adult acute lymphoblastic leukaemias (ALLs), usually results in fusion of exons 1-16 of TCF3 (previously E2A) and exons 3-9 of PBX1. However, some t(1;19)-positive ALLs are negative for this chimaera. We here report an alternative TCF3/PBX1 transcript, fusing exon 17 of TCF3 with exon 5 of PBX1, in a paediatric t(1;19)-positive ALL. The different breakpoints made this hybrid undetectable by reverse transcription polymerase chain reaction using standard TCF3 and PBX1 primers. Hence, ALLs with t(1;19) that test negative for TCF3/PBX1 should be analysed further before excluding this alternative fusion. Furthermore, we have characterised the genomic translocation breakpoints in eight TCF3/PBX1-positive ALLs; four cases with a balanced t(1;19) and four with an unbalanced der(19) t(1;19). It has previously been suggested that the breakpoints are clustered, particularly in TCF3, and that N-nucleotides are frequently present in the fusion junctions. Three of seven investigated TCF3 intron 16 breakpoints were within the previously described 14 base pair-cluster, and all but two junctions harboured N-nucleotides. The PBX1 breakpoints were more dispersed, although still clustered in two regions. This confirms that most t(1;19) rearrangements may arise by a combination of illegitimate V(D)J recombination and nonhomologous end joining.
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| 9. |
- Pettersson, Helen, et al.
(författare)
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Arsenic trioxide and neuroblastoma cytotoxicity.
- 2007
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Ingår i: Journal of Bioenergetics and Biomembranes. - : Springer Science and Business Media LLC. - 1573-6881 .- 0145-479X. ; 39:1, s. 35-41
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Forskningsöversikt (refereegranskat)abstract
- The majority of aggressive forms of the childhood tumor neuroblastoma can with current treatment protocols not be cured and possess a major challenge in pediatric oncology. After initial rounds of chemotherapy, surgery and irradiation, which in most cases result in tumor regression, these aggressive neuroblastomas relapse and frequently develop drug resistance. As approximately 50% of the children with neuroblastoma have an aggressive form, there is a compelling demand for new treatment strategies. Arsenic trioxide has the capacity to kill multidrug-resistant neuro-blastoma cells in vitro and in vivo and the drug is currently being evaluated in clinical trials. In this report we discuss the background to the use of arsenic trioxide in cancer therapy and the currently known mechanisms by which arsenic trioxide kills human neuroblastoma cells.
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| 10. |
- Pietras, Alexander, et al.
(författare)
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High levels of HIF-2alpha highlight an immature neural crest-like neuroblastoma cell cohort located in a perivascular niche.
- 2008
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417. ; 214:4, s. 482-488
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Tidskriftsartikel (refereegranskat)abstract
- High HIF-2alpha protein levels in the sympathetic nervous system-derived childhood tumour neuroblastoma as well as immature phenotype correlate to unfavourable outcome. Here we show that a small subset of perivascularly located, strongly HIF-2alpha-positive tumour cells (MYCN amplified) lacks expression of differentiation markers, but expresses neural crest and early sympathetic progenitor marker genes such as Notch-1, HES-1, c-Kit, dHAND, and vimentin. HIF-2alpha- and CD68-positive tumour-associated macrophages were frequently found close to the immature and HIF-2alpha-positive neuroblastoma cells and as VEGF levels are high in the perivascular niche, we hypothesize that neuroblastoma neural crest-like cells and macrophages cooperate to facilitate angiogenesis and thereby contribute to the aggressive neuroblastoma phenotype. Copyright (c) 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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