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Bertil Johansson - One of the best experts on this subject based on the ideXlab platform.
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constitutional Trisomy 8 mosaicism as a model for epigenetic studies of aneuploidy
Epigenetics & Chromatin, 2013Co-Authors: Josef Davidsson, Srinivas Veerla, Bertil JohanssonAbstract:To investigate epigenetic patterns associated with aneuploidy we used constitutional Trisomy 8 mosaicism (CT8M) as a model, enabling analyses of single cell clones, harboring either Trisomy or disomy 8, from the same patient; this circumvents any bias introduced by using cells from unrelated, healthy individuals as controls. We profiled gene and miRNA expression as well as genome-wide and promoter specific DNA methylation and hydroxymethylation patterns in trisomic and disomic fibroblasts, using microarrays and methylated DNA immunoprecipitation. Trisomy 8-positive fibroblasts displayed a characteristic expression and methylation phenotype distinct from disomic fibroblasts, with the majority (65%) of chromosome 8 genes in the trisomic cells being overexpressed. However, 69% of all deregulated genes and non-coding RNAs were not located on this chromosome. Pathway analysis of the deregulated genes revealed that cancer, genetic disorder, and hematopoiesis were top ranked. The Trisomy 8-positive cells displayed depletion of 5-hydroxymethylcytosine and global hypomethylation of gene-poor regions on chromosome 8, thus partly mimicking the inactivated X chromosome in females. Trisomy 8 affects genes situated also on other chromosomes which, in cooperation with the observed chromosome 8 gene dosage effect, has an impact on the clinical features of CT8M, as demonstrated by the pathway analysis revealing key features that might explain the increased incidence of hematologic malignancies in CT8M patients. Furthermore, we hypothesize that the general depletion of hydroxymethylation and global hypomethylation of chromosome 8 may be unrelated to gene expression regulation, instead being associated with a general mechanism of chromatin processing and compartmentalization of additional chromosomes.
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Trisomy 8 as the sole chromosomal aberration in acute myeloid leukemia and myelodysplastic syndromes
Pathologie Biologie, 2007Co-Authors: Kajsa Paulsson, Bertil JohanssonAbstract:Trisomy 8 as the sole abnormality is the most common karyotypic finding in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), occurring in approximately 5% and 10% of the cytogenetically abnormal cases, respectively. However, despite the high frequency of +8, much remains to be elucidated as regards its epidemiology, etiology, clinical impact, association with other chromosomal abnormalities, cell of origin, and functional and pathogenetic consequences. Here, we summarize and review these various aspects of Trisomy 8, focusing on AMLs and MDS harboring this abnormality as a single change.
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high resolution genome wide array based comparative genome hybridization reveals cryptic chromosome changes in aml and mds cases with Trisomy 8 as the sole cytogenetic aberration
Leukemia, 2006Co-Authors: Kajsa Paulsson, Markus Heidenblad, Bodil Strombeck, Johan Staaf, Goran Jonsson, Ake Borg, Thoas Fioretos, Bertil JohanssonAbstract:Although Trisomy 8 as the sole chromosome aberration is the most common numerical abnormality in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), little is known about its pathogenetic effects. Considering that +8 is a frequent secondary change in AML/MDS, cryptic--possibly primary--genetic aberrations may occur in cases with Trisomy 8 as the apparently single anomaly. However, no such hidden anomalies have been reported. We performed a high-resolution genome-wide array-based comparative genome hybridization (array CGH) analysis of 10 AML/MDS cases with isolated +8, utilizing a 32K bacterial artificial chromosome array set, providing >98% coverage of the genome with a resolution of 100 kb. Array CGH revealed intrachromosomal imbalances, not corresponding to known genomic copy number polymorphisms, in 4/10 cases, comprising nine duplications and hemizygous deletions ranging in size from 0.5 to 2.2 Mb. A 1.8 Mb deletion at 7p14.1, which had occurred prior to the +8, was identified in MDS transforming to AML. Furthermore, a deletion including ETV6 was present in one case. The remaining seven imbalances involved more than 40 genes. The present results show that cryptic genetic abnormalities are frequent in Trisomy 8-positive AML/MDS cases and that +8 as the sole cytogenetic aberration is not always the primary genetic event.
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high resolution genome wide array based comparative genome hybridization reveals cryptic chromosome changes in aml and mds cases with Trisomy 8 as the sole cytogenetic aberration
Blood, 2005Co-Authors: Kajsa Paulsson, Markus Heidenblad, Bodil Strombeck, Ake Borg, Thoas Fioretos, Bertil JohanssonAbstract:Although Trisomy 8 as the sole chromosome aberration is the most common numerical abnormality in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), next to nothing is known about its pathogenetic effects. Considering that +8 is a frequent secondary change in AML and MDS, cryptic - and possibly primary - genetic aberrations may occur in cases with Trisomy 8 as the apparently single anomaly. To date, however, no such hidden anomalies have been reported. We performed a high resolution genome-wide array-based comparative genome hybridization (array CGH) analysis of ten AML/MDS cases with isolated +8, using an array set containing >30,000 BAC and PAC clones. Array CGH revealed intra-chromosomal imbalances, not corresponding to known genomic polymorphisms, in 5/10 cases, comprising ten duplications and hemizygous deletions ranging in size from 0.5 to 2.2 Mb. Most notably, a 1.8 Mb hemizygous deletion at 7p14.1, which had occurred prior to the +8, was identified in one MDS transforming to AML. Furthermore, a hemizygous deletion at 12p13.2, including ETV6 , was present in one case. The remaining eight imbalances involved more than 40 genes. The present results show that cryptic genetic abnormalities are frequent in Trisomy 8-positive AML and MDS cases and that +8 as the sole cytogenetic aberration is not always the primary genetic event.
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Trisomy 8 as the sole chromosomal aberration in myelocytic malignancies a multicolor and locus specific fluorescence in situ hybridization study
Cancer Genetics and Cytogenetics, 2003Co-Authors: Kajsa Paulsson, Bodil Strombeck, Thoas Fioretos, Nils Mauritzson, Hans J Tanke, Bertil JohanssonAbstract:Trisomy 8 is the most common chromosomal aberration in myelocytic malignancies, occurring both as a sole change as well as in addition to other abnormalities. In spite of this, next to nothing is known about its pathogenetic importance or its molecular genetic consequences. Possible mechanisms involved in the transformation process include dosage effects of genes mapping to chromosome 8 and presence of specific mutations or cryptic fusion genes on the duplicated chromosome. In the latter case, +8 would be secondary to a cryptic primary rearrangement and not involved in leukemogenesis as such, but rather in tumor evolution. Although hidden genetic changes have been found in some trisomies, for example, mutations in KIT in acute myelocytic leukemia (AML) with +4 and in MET in hereditary papillary kidney carcinoma with Trisomy 7, none associated with +8 have so far been discovered. To address this issue, we have investigated a total of 13 cases of AML, myelodysplastic syndromes, and chronic myeloproliferative disorders with Trisomy 8 as the sole chromosomal anomaly. All cases were studied by combined binary ratio multicolor fluorescence in situ hybridization (FISH) and with FISH using locus-specific probes for both arms of chromosome 8, the subtelomeric regions of 8p and 8q, and the leukemia-associated genes FGFR1, MOZ, ETO, and MYC. No cryptic changes were detected, thus excluding the possibility of gross genetic rearrangements or aberrations involving these loci on chromosome 8.
L J Medeiros - One of the best experts on this subject based on the ideXlab platform.
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clinical significance of Trisomy 8 that emerges during therapy in chronic myeloid leukemia
Blood Cancer Journal, 2016Co-Authors: Wei Wang, Z Chen, Cheng Cameron Yin, S Bai, Carlos E Buesoramos, L J MedeirosAbstract:Chronic myeloid leukemia (CML) is defined by t(9;22)(q34;q11), a genetic abnormality producing BCR-ABL1 fusion on derivative chromosome 22.1 At cytogenetic level, t(9;22)(q34;q11) is the sole abnormality in over 90% of patients in chronic phase (CP). As the disease progresses to accelerated phase (AP) and blast phase (BP), clonal evolution occurs commonly with the emergence of additional cytogenetic abnormalities (ACAs). Approximately 30% of patients with CML-AP and 70–80% of patients with CML-BP have ACAs.2, 3, 4 Among various ACAs, Trisomy 8 (+8) and an extra copy of philadelphia chromosome (Ph) are most common.5, 6 Different ACAs have been shown to be associated with different impact on treatment response and survival. Some ACAs are associated with disease progression and treatment resistance, whereas others may simply reflect the genetic instability induced by continuous activation of BCR-ABL1.6, 7, 8 In addition, the interval from initial diagnosis of CML to emergence of ACAs may also be important as the same ACA can have differential impact on tyrosine kinase inhibitor (TKI) treatment and prognosis when it emerges at the time of initial CML diagnosis versus during therapy.6 In the recently updated World Health Organization (WHO) criteria for AP of CML, any new clonal chromosomal abnormality in t(9;22) positive cells that occurs during therapy is considered as a criterion for AP.9
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impact of Trisomy 8 on treatment response and survival of patients with chronic myelogenous leukemia in the era of tyrosine kinase inhibitors
Leukemia, 2015Co-Authors: Wei Lien Wang, Jorge E Cortes, Pei Lin, Joseph D Khoury, Zhenya Tang, Guilin Tang, Jeffrey L Jorgensen, L J MedeirosAbstract:Impact of Trisomy 8 on treatment response and survival of patients with chronic myelogenous leukemia in the era of tyrosine kinase inhibitors
Hakon Reikvam - One of the best experts on this subject based on the ideXlab platform.
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Trisomy 8 in acute myeloid leukemia
Expert Review of Hematology, 2019Co-Authors: Anette Lodvir Hemsing, Randi Hovland, Galina Tsykunova, Hakon ReikvamAbstract:Introduction: Trisomy 8 is one of the most common cytogenetic alterations in acute myeloid leukemia (AML), with a frequency between 10% and 15%.Areas covered: The authors summarize the latest research regarding biological, translational and clinical aspects of Trisomy 8 in AML.Expert opinion: Trisomy 8 can be found together with other karyotypes, although it also occurs as a sole aberration. The last decade's research has brought attention to molecular genetic alterations as strong contributors of leukemogenesis. AML with Trisomy 8 seems to be associated with mutations in DNA methylation genes, spliceosome complex genes, and myeloid transcription factor genes, and these alterations probably have stronger implication for leukemic pathogenesis, treatment and hence prognosis, than the existence of Trisomy 8 itself. Especially mutations in the RUNX1 and ASXL1 genes occur in high frequencies, and search for such mutations should be mandatory part of the diagnostic workup. AML with Trisomy 8 is classified as intermediate-risk AML after recent European Leukemia Net (ELN) classification, and hence allogenic hematopoietic stem cell transplantation (Allo-HSCT) should be consider as consolidation therapy for this patient group.Trisomy 8 is frequently occurring in AML, although future molecular genetic workup should be performed, to optimize the diagnosis and treatment of these patients.
P Bernard - One of the best experts on this subject based on the ideXlab platform.
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a second case of Trisomy 8 in philadelphia chromosome ph negative cells during the course of ph positive chronic myelocytic leukemia
Genes Chromosomes and Cancer, 1993Co-Authors: C Bilhounabera, G Marit, I Devianne, F Viard, S Salzes, M Montastruc, M Renoux, A Broustet, J Reiffers, P BernardAbstract:A Ph-positive CML patient who had received a peripheral blood stem cell autograft in chronic phase demonstrated a transient regression of the Ph-positive clone with the concurrent appearance of another clone with Trisomy 8. This latter clone disappeared when the patient received alpha-interferon.
Kajsa Paulsson - One of the best experts on this subject based on the ideXlab platform.
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Trisomy 8 as the sole chromosomal aberration in acute myeloid leukemia and myelodysplastic syndromes
Pathologie Biologie, 2007Co-Authors: Kajsa Paulsson, Bertil JohanssonAbstract:Trisomy 8 as the sole abnormality is the most common karyotypic finding in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), occurring in approximately 5% and 10% of the cytogenetically abnormal cases, respectively. However, despite the high frequency of +8, much remains to be elucidated as regards its epidemiology, etiology, clinical impact, association with other chromosomal abnormalities, cell of origin, and functional and pathogenetic consequences. Here, we summarize and review these various aspects of Trisomy 8, focusing on AMLs and MDS harboring this abnormality as a single change.
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high resolution genome wide array based comparative genome hybridization reveals cryptic chromosome changes in aml and mds cases with Trisomy 8 as the sole cytogenetic aberration
Leukemia, 2006Co-Authors: Kajsa Paulsson, Markus Heidenblad, Bodil Strombeck, Johan Staaf, Goran Jonsson, Ake Borg, Thoas Fioretos, Bertil JohanssonAbstract:Although Trisomy 8 as the sole chromosome aberration is the most common numerical abnormality in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), little is known about its pathogenetic effects. Considering that +8 is a frequent secondary change in AML/MDS, cryptic--possibly primary--genetic aberrations may occur in cases with Trisomy 8 as the apparently single anomaly. However, no such hidden anomalies have been reported. We performed a high-resolution genome-wide array-based comparative genome hybridization (array CGH) analysis of 10 AML/MDS cases with isolated +8, utilizing a 32K bacterial artificial chromosome array set, providing >98% coverage of the genome with a resolution of 100 kb. Array CGH revealed intrachromosomal imbalances, not corresponding to known genomic copy number polymorphisms, in 4/10 cases, comprising nine duplications and hemizygous deletions ranging in size from 0.5 to 2.2 Mb. A 1.8 Mb deletion at 7p14.1, which had occurred prior to the +8, was identified in MDS transforming to AML. Furthermore, a deletion including ETV6 was present in one case. The remaining seven imbalances involved more than 40 genes. The present results show that cryptic genetic abnormalities are frequent in Trisomy 8-positive AML/MDS cases and that +8 as the sole cytogenetic aberration is not always the primary genetic event.
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high resolution genome wide array based comparative genome hybridization reveals cryptic chromosome changes in aml and mds cases with Trisomy 8 as the sole cytogenetic aberration
Blood, 2005Co-Authors: Kajsa Paulsson, Markus Heidenblad, Bodil Strombeck, Ake Borg, Thoas Fioretos, Bertil JohanssonAbstract:Although Trisomy 8 as the sole chromosome aberration is the most common numerical abnormality in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), next to nothing is known about its pathogenetic effects. Considering that +8 is a frequent secondary change in AML and MDS, cryptic - and possibly primary - genetic aberrations may occur in cases with Trisomy 8 as the apparently single anomaly. To date, however, no such hidden anomalies have been reported. We performed a high resolution genome-wide array-based comparative genome hybridization (array CGH) analysis of ten AML/MDS cases with isolated +8, using an array set containing >30,000 BAC and PAC clones. Array CGH revealed intra-chromosomal imbalances, not corresponding to known genomic polymorphisms, in 5/10 cases, comprising ten duplications and hemizygous deletions ranging in size from 0.5 to 2.2 Mb. Most notably, a 1.8 Mb hemizygous deletion at 7p14.1, which had occurred prior to the +8, was identified in one MDS transforming to AML. Furthermore, a hemizygous deletion at 12p13.2, including ETV6 , was present in one case. The remaining eight imbalances involved more than 40 genes. The present results show that cryptic genetic abnormalities are frequent in Trisomy 8-positive AML and MDS cases and that +8 as the sole cytogenetic aberration is not always the primary genetic event.
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Trisomy 8 as the sole chromosomal aberration in myelocytic malignancies a multicolor and locus specific fluorescence in situ hybridization study
Cancer Genetics and Cytogenetics, 2003Co-Authors: Kajsa Paulsson, Bodil Strombeck, Thoas Fioretos, Nils Mauritzson, Hans J Tanke, Bertil JohanssonAbstract:Trisomy 8 is the most common chromosomal aberration in myelocytic malignancies, occurring both as a sole change as well as in addition to other abnormalities. In spite of this, next to nothing is known about its pathogenetic importance or its molecular genetic consequences. Possible mechanisms involved in the transformation process include dosage effects of genes mapping to chromosome 8 and presence of specific mutations or cryptic fusion genes on the duplicated chromosome. In the latter case, +8 would be secondary to a cryptic primary rearrangement and not involved in leukemogenesis as such, but rather in tumor evolution. Although hidden genetic changes have been found in some trisomies, for example, mutations in KIT in acute myelocytic leukemia (AML) with +4 and in MET in hereditary papillary kidney carcinoma with Trisomy 7, none associated with +8 have so far been discovered. To address this issue, we have investigated a total of 13 cases of AML, myelodysplastic syndromes, and chronic myeloproliferative disorders with Trisomy 8 as the sole chromosomal anomaly. All cases were studied by combined binary ratio multicolor fluorescence in situ hybridization (FISH) and with FISH using locus-specific probes for both arms of chromosome 8, the subtelomeric regions of 8p and 8q, and the leukemia-associated genes FGFR1, MOZ, ETO, and MYC. No cryptic changes were detected, thus excluding the possibility of gross genetic rearrangements or aberrations involving these loci on chromosome 8.
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the incidence of Trisomy 8 as a sole chromosomal aberration in myeloid malignancies varies in relation to gender age prior iatrogenic genotoxic exposure and morphology
Cancer Genetics and Cytogenetics, 2001Co-Authors: Kajsa Paulsson, Thoas Fioretos, Torbjorn Sall, Felix Mitelman, Bertil JohanssonAbstract:Although Trisomy 8 as a sole change is one of the most common chromosomal abnormalities in myeloid malignancies, it is largely unknown if the incidence of this aberration is influenced by other factors of clinical importance. In the present study, the frequencies of isolated +8 in relation to gender, age, previous treatment with chemo- or radiotherapy, and morphologic subtype were ascertained in published, as well as in our own unpublished, cases of acute myeloid leukemia (AML; n=4,246), myelodysplastic syndromes (MDS; n=1,817), and chronic myeloproliferative disorders (MPD; n=530). The frequencies of +8 were higher in MDS and MPD than in AML (7.5% vs. 5.6%; P<0.01) and varied among the morphologic subtypes of AML and MDS (P<0.001 and P<0.05, respectively). Trisomy 8 was more common in women than in men with MPD (11% vs. 5.1%; P<0.05). Furthermore, the frequencies of +8 were higher in de novo AML and MDS than in treatment-related cases (6.0% vs. 2.8%; P<0.01 and 8.6% vs. 1.5%; P<0.001, respectively). The incidence also varied significantly with age in AML (P<0.001), being more common in elderly patients. Although the causes for this frequency heterogeneity remain to be elucidated, possible explanations may include different environmental exposures affecting the origin of +8 in AML, MDS, and MPD and the presence of different underlying cryptic primary aberrations.
