29 results on '"Gisselsson, David"'
Search Results
2. Delineating the intra-patient heterogeneity of molecular alterations in treatment-naïve colorectal cancer with peritoneal carcinomatosis
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Siesing, Christina, Petersson, Alexandra, Ulfarsdottir, Thora, Chattopadhyay, Subhayan, Nodin, Björn, Eberhard, Jakob, Brändstedt, Jenny, Syk, Ingvar, Gisselsson, David, and Jirström, Karin
- Abstract
In a non-negligible number of patients with metastatic colorectal cancer (mCRC), the peritoneum is the predominant site of dissemination. Cure can be achieved by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), but this procedure is associated with long-term morbidity and high relapse rates. Thus, there is a pressing need for improved therapeutic strategies and complementary biomarkers. The present study explored the molecular heterogeneity in mCRC with peritoneal carcinomatosis (PC), and the potential clinical implications thereof. Multi-region immunohistochemical profiling and deep targeted DNA-sequencing was performed on chemotherapy-naïve tumours from seven patients with synchronous colorectal PC who underwent CRS and HIPEC. In total, 88 samples (5-19 per patient) were analysed, representing primary tumour, lymph node metastases, tumour deposits, PC and liver metastases. Expression of special AT-rich sequence-binding protein 2 (SATB2), a marker of colorectal lineage, was lacking in the majority of cases, and a conspicuous intra-patient heterogeneity was denoted for expression of the proposed prognostic and predictive biomarker RNA-binding motif protein 3 (RBM3). Loss of mismatch repair proteins MLH1 and PSM2, observed in one case, was concordant with microsatellite instability and the highest tumour mutational burden. When present in a patient, mutations in key CRC driver genes, i.e., KRAS, APCand TP53, were homogenously distributed across all samples, while less common mutations were more heterogenous. On the same note, copy number variations showed intra-patient as well inter-patient heterogeneity. In two out of seven cases, hierarchical clustering revealed that samples from the PC and lymph node metastases were more similar to each other than to the primary tumour. In summary, these findings should encourage additional studies addressing the potential distinctiveness of mCRC with PC, which might pave the way for improved personalized treatment of these patients.
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- 2022
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3. Delineating the intra-patient heterogeneity of molecular alterations in treatment-naïve colorectal cancer with peritoneal carcinomatosis
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Siesing, Christina, Petersson, Alexandra, Ulfarsdottir, Thora, Chattopadhyay, Subhayan, Nodin, Björn, Eberhard, Jakob, Brändstedt, Jenny, Syk, Ingvar, Gisselsson, David, and Jirström, Karin
- Abstract
In a non-negligible number of patients with metastatic colorectal cancer (mCRC), the peritoneum is the predominant site of dissemination. Cure can be achieved by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), but this procedure is associated with long-term morbidity and high relapse rates. Thus, there is a pressing need for improved therapeutic strategies and complementary biomarkers. The present study explored the molecular heterogeneity in mCRC with peritoneal carcinomatosis (PC), and the potential clinical implications thereof. Multi-region immunohistochemical profiling and deep targeted DNA-sequencing was performed on chemotherapy-naïve tumours from seven patients with synchronous colorectal PC who underwent CRS and HIPEC. In total, 88 samples (5-19 per patient) were analysed, representing primary tumour, lymph node metastases, tumour deposits, PC and liver metastases. Expression of special AT-rich sequence-binding protein 2 (SATB2), a marker of colorectal lineage, was lacking in the majority of cases, and a conspicuous intra-patient heterogeneity was denoted for expression of the proposed prognostic and predictive biomarker RNA-binding motif protein 3 (RBM3). Loss of mismatch repair proteins MLH1 and PSM2, observed in one case, was concordant with microsatellite instability and the highest tumour mutational burden. When present in a patient, mutations in key CRC driver genes, i.e., KRAS, APCand TP53, were homogenously distributed across all samples, while less common mutations were more heterogenous. On the same note, copy number variations showed intra-patient as well inter-patient heterogeneity. In two out of seven cases, hierarchical clustering revealed that samples from the PC and lymph node metastases were more similar to each other than to the primary tumour. In summary, these findings should encourage additional studies addressing the potential distinctiveness of mCRC with PC, which might pave the way for improved personalized treatment of these patients.
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- 2022
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4. Weaponized genomics: potential threats to international and human security
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Chattopadhyay, Subhayan, Ingesson, Tony, Rinaldi, Alberto, Larsson, Oscar, Widen, J. J., Almqvist, Jessica, and Gisselsson, David
- Abstract
Genetic technologies are revolutionizing human health. In parallel, geopolitical instability has prompted renewed discussions on the risks of DNA technology being weaponized in international conflict. With today’s changing security environment, we argue that risk assessments must be broadened from genetically targeted weapons to a series of new domains.
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- 2024
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5. Implementing precision medicine in a regionally organized healthcare system in Sweden
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Fioretos, Thoas, Wirta, Valtteri, Cavelier, Lucia, Berglund, Eva, Friedman, Mikaela, Akhras, Michael, Botling, Johan, Ehrencrona, Hans, Engstrand, Lars, Helenius, Gisela, Fagerqvist, Therese, Gisselsson, David, Gruvberger-Saal, Sofia, Gyllensten, Ulf, Heidenblad, Markus, Höglund, Kina, Jacobsson, Bo, Johansson, Maria, Johansson, Åsa, Soller, Maria Johansson, Landström, Maréne, Larsson, Pär, Levin, Lars-Åke, Lindstrand, Anna, Lovmar, Lovisa, Lyander, Anna, Melin, Malin, Nordgren, Ann, Nordmark, Gunnel, Mölling, Paula, Palmqvist, Lars, Palmqvist, Richard, Repsilber, Dirk, Sikora, Per, Stenmark, Bianca, Söderkvist, Peter, Stranneheim, Henrik, Strid, Tobias, Wheelock, Craig E., Wadelius, Mia, Wedell, Anna, Edsjö, Anders, and Rosenquist, Richard
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- 2022
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6. A Gradual Transition Toward Anaplasia in Wilms Tumor Through Tolerance to Genetic Damage
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Uno, Kaname, Rastegar, Bahar, Jansson, Caroline, Durand, Geoffroy, Valind, Anders, Chattopadhyay, Subhayan, Bertolotti, Alessia, Ciceri, Sara, Spreafico, Filippo, Collini, Paola, Perotti, Daniela, Mengelbier, Linda Holmquist, and Gisselsson, David
- Abstract
Patients with Wilms tumor (WT) in general have excellent survival, but the prognosis of patients belonging to the subgroup of WT with diffuse anaplasia (DA) is poor due to frequent resistance to chemotherapy. We hypothesized that DA WT cells might undergo changes, such as acquiring a persistent tolerance to DNA damage and copy number aberrations (CNAs), which could eventually lead to their resistance to chemotherapy treatment. Tissue sections from chemotherapy-treated DA WTs (n = 12) were compared with chemotherapy-treated nonanaplastic WTs (n = 15) in a tissue microarray system, enabling analysis of 769 tumor regions. All regions were scored for anaplastic features and immunohistochemistry was used to quantify p53 expression, proliferation index (Ki67), and DNA double-strand breaks (γH2AX). CNAs were assessed by array-based genotyping and TP53mutations using targeted sequencing. Proliferation index and the frequency of DNA double-strand breaks (γH2AX dot expression) increased with higher anaplasia scores. Almost all (95.6%) areas with full-scale anaplasia had TP53mutations or loss of heterozygosity, along with an increased amount of CNAs. Interestingly, areas with wild-type TP53with loss of heterozygosity and only one feature of anaplasia (anaplasia score 1) also had significantly higher proliferation indices, more DNA double-strand breaks, and more CNAs than regions without any anaplastic features (score 0); such areas may be preanaplastic cell populations under selective pressure for TP53mutations. In conclusion, we suggest that chemoresistance of DA WTs may be partly explained by a high proliferative capability of anaplastic cells, which also have a high burden of double-stranded DNA breaks and CNAs, and that there is a gradual emergence of anaplasia in WT.
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- 2024
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7. Macrophage infiltration promotes regrowth in MYCN-amplified neuroblastoma after chemotherapy
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Valind, Anders, Verhoeven, Bronte Manouk, Enoksson, Jens, Karlsson, Jenny, Christensson, Gustav, Mañas, Adriana, Aaltonen, Kristina, Jansson, Caroline, Bexell, Daniel, Baryawno, Ninib, Gisselsson, David, and Hagerling, Catharina
- Abstract
ABSTRACTDespite aggressive treatment, the 5-year event-free survival rate for children with high-risk neuroblastoma is <50%. While most high-risk neuroblastoma patients initially respond to treatment, often with complete clinical remission, many eventually relapse with therapy-resistant tumors. Novel therapeutic alternatives that prevent the recurrence of therapy-resistant tumors are urgently needed. To understand the adaptation of neuroblastoma under therapy, we analyzed the transcriptomic landscape in 46 clinical tumor samples collected before (PRE) or after (POST) treatment from 22 neuroblastoma patients. RNA sequencing revealed that many of the top-upregulated biological processes in POST MYCNamplified (MNA+) tumors compared to PRE MNA+tumors were immune-related, and there was a significant increase in numerous genes associated with macrophages. The infiltration of macrophages was corroborated by immunohistochemistry and spatial digital protein profiling. Moreover, POST MNA+tumor cells were more immunogenic compared to PRE MNA+tumor cells. To find support for the macrophage-induced outgrowth of certain subpopulations of immunogenic tumor cells following treatment, we examined the genetic landscape in multiple clinical PRE and POST tumor samples from nine neuroblastoma patients revealing a significant correlation between an increased amount of copy number aberrations (CNA) and macrophage infiltration in POST MNA+tumor samples. Using an in vivoneuroblastoma patient-derived xenograft (PDX) chemotherapy model, we further show that inhibition of macrophage recruitment with anti-CSF1R treatment prevents the regrowth of MNA+tumors following chemotherapy. Taken together, our work supports a therapeutic strategy for fighting the relapse of MNA+neuroblastoma by targeting the immune microenvironment.
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- 2023
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8. Changes in the Prevalence of Embryologic Remnants in Umbilical Cord With Gestational Age
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Grottling, Emma and Gisselsson, David
- Abstract
The aim of this study was to examine the prevalence of embryologic remnants in umbilical cords of different gestational ages. Sections from 392 umbilical cords were examined using light microscopy. Of these, 52% contained at least 1 remnant, most commonly of the allantoic duct type. Although there was a significant decrease in vitelline duct remnants over increasing gestational age, from 11% at weeks 11–25 to 1.6% at weeks 36–42 (P= .009; χ2test), the allantoic duct remnants remained constant in prevalence irrespective of gestational age.
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- 2019
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9. The Cellular Architectures of Hypospadias
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Nozohoor Ekmark, Ann, Grelaud, Diane, Hansson, Emma, Svensson, Henry, Arnbjörnsson, Einar, and Gisselsson, David
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- 2020
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10. Four evolutionary trajectories underlie genetic intratumoral variation in childhood cancer
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Karlsson, Jenny, Valind, Anders, Holmquist Mengelbier, Linda, Bredin, Sofia, Cornmark, Louise, Jansson, Caroline, Wali, Amina, Staaf, Johan, Viklund, Björn, Øra, Ingrid, Börjesson, Anna, Backman, Torbjörn, Braekeveldt, Noémie, Sandstedt, Bengt, Pal, Niklas, Isaksson, Anders, Lackner, Barbara, Jonson, Tord, Bexell, Daniel, and Gisselsson, David
- Abstract
A major challenge to personalized oncology is that driver mutations vary among cancer cells inhabiting the same tumor. Whether this reflects principally disparate patterns of Darwinian evolution in different tumor regions has remained unexplored1–5. We mapped the prevalence of genetically distinct clones over 250 regions in 54 childhood cancers. This showed that primary tumors can simultaneously follow up to four evolutionary trajectories over different anatomic areas. The most common pattern consists of subclones with very few mutations confined to a single tumor region. The second most common is a stable coexistence, over vast areas, of clones characterized by changes in chromosome numbers. This is contrasted by a third, less frequent, pattern where a clone with driver mutations or structural chromosome rearrangements emerges through a clonal sweep to dominate an anatomical region. The fourth and rarest pattern is the local emergence of a myriad of clones with TP53inactivation. Death from disease was limited to tumors exhibiting the two last, most dynamic patterns. Multiregional analysis in 54 childhood cancers highlights four evolutionary patterns of intratumoral variation. Multiple patterns are often found in the same tumor, suggesting that tumors follow different evolutionary strategies concurrently.
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- 2018
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11. Mosaicism in health and disease — clones picking up speed
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Forsberg, Lars A., Gisselsson, David, and Dumanski, Jan P.
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Post-zygotic variation refers to genetic changes that arise in the soma of an individual and that are not usually inherited by the next generation. Although there is a paucity of research on such variation, emerging studies show that it is common: individuals are complex mosaics of genetically distinct cells, to such an extent that no two somatic cells are likely to have the exact same genome. Although most types of mutation can be involved in post-zygotic variation, structural genetic variants are likely to leave the largest genomic footprint. Somatic variation has diverse physiological roles and pathological consequences, particularly when acquired variants influence the clonal trajectories of the affected cells. Post-zygotic variation is an important confounder in medical genetic testing and a promising avenue for research: future studies could involve analyses of sorted and single cells from multiple tissue types to fully explore its potential.
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- 2017
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12. The immune cell atlas of human neuroblastoma
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Verhoeven, Bronte Manouk, Mei, Shenglin, Olsen, Thale Kristin, Gustafsson, Karin, Valind, Anders, Lindström, Axel, Gisselsson, David, Fard, Shahrzad Shirazi, Hagerling, Catharina, Kharchenko, Peter V., Kogner, Per, Johnsen, John Inge, and Baryawno, Ninib
- Abstract
Understanding the complete immune cell composition of human neuroblastoma (NB) is crucial for the development of immunotherapeutics. Here, we perform single-cell RNA sequencing (scRNA-seq) on 19 human NB samples coupled with multiplex immunohistochemistry, survival analysis, and comparison with normal fetal adrenal gland data. We provide a comprehensive immune cell landscape and characterize cell-state changes from normal tissue to NB. Our analysis reveals 27 immune cell subtypes, including distinct subpopulations of myeloid, NK, B, and T cells. Several different cell types demonstrate a survival benefit. In contrast to adult cancers and previous NB studies, we show an increase in inflammatory monocyte cell state when contrasting normal and tumor tissue, while no differences in cytotoxicity and exhaustion score for T cells, nor in Treg activity, are observed. Our receptor-ligand interaction analysis reveals a highly complex interactive network of the NB microenvironment from which we highlight several interactions that we suggest for future therapeutic studies.
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- 2022
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13. Cancer – An Insurgency of Clones
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Gisselsson, David and Egnell, Robert
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Oncological therapy resembles a military force that eliminates the central power of a country (dominant clone of a cancer) to create a vacuum where insurgents (subclones) thrive and instigate rebellion (relapse). We suggest that military counterinsurgency doctrine can inspire a discussion of cancer that uniquely embraces both cancer cell evolution and tumour microenvironment.
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- 2017
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14. snoRNPs Regulate Telomerase Activity in Neuroblastoma and Are Associated with Poor Prognosis
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von Stedingk, Kristoffer, Koster, Jan, Piqueras, Marta, Noguera, Rosa, Navarro, Samuel, Påhlman, Sven, Versteeg, Rogier, Øra, Ingrid, Gisselsson, David, Lindgren, David, and Axelson, Håkan
- Abstract
Amplification of the MYCNoncogene is strongly associated with poor prognosis in neuroblastoma (NB). In addition to MYCNamplification, many studies have focused on identifying patients with a poor prognosis based on gene expression profiling. The majority of prognostic signatures today are comprised of large gene lists limiting their clinical application. In addition, although of prognostic significance,most of these signatures fail to identify cellular processes that can explain their relation to prognosis. Here, we determined prognostically predictive genes in a data set containing 251 NBs. Gene Ontology analysis was performed on significant genes with a positive hazard ratio to search for cellular processes associated with poor prognosis. An enrichment in ribonucleoproteins (RNPs) was found. Genes involved in the stabilization and formation of the central small nucleolar RNP (snoRNP) complex were scrutinized using a backward conditional Cox regression resulting in an snoRNP signature consisting of three genes: DKC1, NHP2, and GAR1. The snoRNP signature significantly and independently predicted prognosis when compared to the established clinical risk factors. Association of snoRNP protein expression and prognosis was confirmed using tissue microarrays. Knockdown of snoRNP expression in NB cell lines resulted in reduced telomerase activity and an increase in anaphase bridge frequency. In addition, in patient material, expression of the snoRNP complex was significantly associated with telomerase activity, occurrence of segmental aberrations, and expression-based measurements of chromosomal instability. Together, these results underscore the prognostic value of snoRNP complex expression in NB and suggest a role for snoRNPs in telomere maintenance and genomic stability.
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- 2013
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15. Biphasic, Hyperdiploid Breast Tumors in Children
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Walther, Charles, Gisselsson, David, Magnusson, Linda, Nilsson, Jenny, Grabau, Dorthe, Kullendorff, Carl-Magnus, Nord, Karolin H., and Mertens, Fredrik
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The differentiation between a giant fibroadenoma and a phyllodes tumor can be a precarious diagnostic task. However, the distinction between the 2 lesions is important to make, especially since the latter can be malignant and consequently the prognoses differ.
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- 2013
16. Deletions of 16q in Wilms Tumors Localize to Blastemal-Anaplastic Cells and Are Associated with Reduced Expression of the IRXB Renal Tubulogenesis Gene Cluster
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Mengelbier, Linda Holmquist, Karlsson, Jenny, Lindgren, David, Øra, Ingrid, Isaksson, Margareth, Frigyesi, Ildiko, Frigyesi, Attila, Bras, Johannes, Sandstedt, Bengt, and Gisselsson, David
- Abstract
Wilms tumor is the most common pediatric renal neoplasm, but few molecular prognostic markers have been identified for this tumor. Somatic deletion in the long arm of chromosome 16 (16q) is known to predict a less favorable outcome in Wilms tumor, but the underlying molecular mechanisms are not known. We show that 16q deletions are typically confined to immature anaplastic-blastic tumor elements, while deletions are absent in maturing tumor components. The smallest region of deletion overlap mapped to a 1.8-Mb segment containing the IRXB gene cluster including IRX3, IRX5, and IRX6, of which IRX3is a recently identified regulator of tubular maturation during nephrogenesis. Tumors with 16q deletion showed a lower overall mRNA expression of IRXB genes, and 16q-deleted tumor cells failed to express IRX3 while it was expressed in differentiating tubular tumor elements with intact 16q. Consistent with a role for IRX3in tubular differentiation, gene sets linked to Notch signaling, Rho signaling, and ion channel activity were enriched in tumors with high IRX3expression, while WTs with low expression were enriched for gene sets linked to cell cycle progression. Low mRNA levels of IRXB genes were associated with diffuse anaplasia, high-stage disease, and death. A disturbed balance between tubular differentiation and self-renewal of anaplastic-blastic elements may thus be one mechanism linking 16q deletion to adverse outcome in Wilms tumor.
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- 2010
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17. Modeling the human 8p11-myeloproliferative syndrome in immunodeficient mice
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Ågerstam, Helena, Järås, Marcus, Andersson, Anna, Johnels, Petra, Hansen, Nils, Lassen, Carin, Rissler, Marianne, Gisselsson, David, Olofsson, Tor, Richter, Johan, Fan, Xiaolong, Ehinger, Mats, and Fioretos, Thoas
- Abstract
The 8p11 myeloproliferative syndrome (EMS), also referred to as stem cell leukemia/lymphoma, is a chronic myeloproliferative disorder that rapidly progresses into acute leukemia. Molecularly, EMS is characterized by fusion of various partner genes to the FGFR1 gene, resulting in constitutive activation of the tyrosine kinases in FGFR1. To date, no previous study has addressed the functional consequences of ectopic FGFR1 expression in the potentially most relevant cellular context, that of normal primary human hematopoietic cells. Herein, we report that expression of ZMYM2/FGFR1 (previously known as ZNF198/FGFR1) or BCR/FGFR1 in normal human CD34+ cells from umbilical-cord blood leads to increased cellular proliferation and differentiation toward the erythroid lineage in vitro. In immunodeficient mice, expression of ZMYM2/FGFR1 or BCR/FGFR1 in human cells induces several features of human EMS, including expansion of several myeloid cell lineages and accumulation of blasts in bone marrow. Moreover, bone marrow fibrosis together with increased extramedullary hematopoiesis is observed. This study suggests that FGFR1 fusion oncogenes, by themselves, are capable of initiating an EMS-like disorder, and provides the first humanized model of a myeloproliferative disorder transforming into acute leukemia in mice. The established in vivo EMS model should provide a valuable tool for future studies of this disorder.
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- 2010
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18. Modeling the human 8p11-myeloproliferative syndrome in immunodeficient mice
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Ågerstam, Helena, Järås, Marcus, Andersson, Anna, Johnels, Petra, Hansen, Nils, Lassen, Carin, Rissler, Marianne, Gisselsson, David, Olofsson, Tor, Richter, Johan, Fan, Xiaolong, Ehinger, Mats, and Fioretos, Thoas
- Abstract
The 8p11 myeloproliferative syndrome (EMS), also referred to as stem cell leukemia/lymphoma, is a chronic myeloproliferative disorder that rapidly progresses into acute leukemia. Molecularly, EMS is characterized by fusion of various partner genes to the FGFR1gene, resulting in constitutive activation of the tyrosine kinases in FGFR1. To date, no previous study has addressed the functional consequences of ectopic FGFR1expression in the potentially most relevant cellular context, that of normal primary human hematopoietic cells. Herein, we report that expression of ZMYM2/FGFR1(previously known as ZNF198/FGFR1) or BCR/FGFR1in normal human CD34+cells from umbilical-cord blood leads to increased cellular proliferation and differentiation toward the erythroid lineage in vitro. In immunodeficient mice, expression of ZMYM2/FGFR1or BCR/FGFR1in human cells induces several features of human EMS, including expansion of several myeloid cell lineages and accumulation of blasts in bone marrow. Moreover, bone marrow fibrosis together with increased extramedullary hematopoiesis is observed. This study suggests that FGFR1fusion oncogenes, by themselves, are capable of initiating an EMS-like disorder, and provides the first humanized model of a myeloproliferative disorder transforming into acute leukemia in mice. The established in vivo EMS model should provide a valuable tool for future studies of this disorder.
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- 2010
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19. Mitotic Instability in Cancer: Is There Method in the Madness?
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Gisselsson, David
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It has been known for more than a century that neoplastic cells often exhibit disturbances of the mitotic process, but the causes have only recently been thoroughly explored. In many cancers, a combination of cell cycle checkpoint deficiency and abnormal shortening of telomeres predisposes to unbalanced chromosome segregation at cell division and the development of complex genomic rearrangements. Shortening of telomeric repeats beyond normal limits leads to fusion of chromosome ends and the formation of chromatin bridges at anaphase. In turn, these bridges may trigger at least three types of chromosomes mutation: (1) structural rearrangements of chromosomes through extensive chromatin fragmentation beyond the centromeric sequences, typically leading to the formation of isochromosomes and whole-arm translocations, (2) loss of whole chromosomes through mechanical detachment from the mitotic spindle machinery, and (3) failure of cytokinesis, leading to polyploidisation and supernumerary centrosomes, which may in turn orchestrate multipolar spindle configurations at a subsequent mitosis. Anaphase bridging rarely hinders further survival of tumour daughter cells. In contrast, multipolar mitoses may lead to extensive reshuffling of chromosome copies that compromise further clonal expansion. The telomere-dependent instability can be partly counteracted by expression of telomerase during tumour progression, but genomic stabilisation is rarely, if ever, complete.
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- 2005
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20. PLAG1Alterations in Lipoblastoma
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Gisselsson, David, Hibbard, Michele K., Dal Cin, Paola, Sciot, Raf, Hsi, Bae-Li, Kozakewich, Harry P., and Fletcher, Jonathan A.
- Abstract
Lipoblastomas are rare soft tissue tumors that occur primarily in young children. They typically contain variably differentiated adipocytes, primitive mesenchymal cells, myxoid matrix, and fibrous trabeculae. Abnormalities in chromosome 8, leading to rearrangements of the PLAG1gene, were demonstrated recently in four lipoblastomas. In the present report, we determine the frequency of PLAG1alterations in 16 lipoblastomas from children aged 13 years or younger, and we also evaluate the stages of lipoblastoma differentiation at which PLAG1genomic alterations are found. Eleven lipoblastomas (69%), including those with either classic or lipoma-like histology, had rearrangements of the 8q12 PLAG1region. Another three lipoblastomas had polysomy for chromosome 8 in the absence of PLAG1rearrangement. Only two cases (13%) lacked a chromosome 8 abnormality. Notably, the lipoblastomas with chromosome 8 polysomy had up to five copies of chromosome 8 as an isolated cytogenetic finding in an otherwise diploid cell. We also demonstrate that PLAG1alterations are found in a spectrum of mesenchymal cell types in lipoblastomas, including lipoblasts, mature adipocytes, primitive mesenchymal cells, and fibroblast-like cells. This finding is consistent with neoplastic origin in a primitive mesenchymal precursor and with variable differentiation to a mature adipocyte end-point. Hence, our studies provide biological validation for the clinical observation that lipoblastomas can evolve into mature, lipoma-like, lesions. They also suggest that PLAG1dosage alterations caused by polysomy 8 might represent an alternative oncogenic mechanism in lipoblastoma.
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- 2001
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21. Refined characterisation of chromosome aberrations in tumours by multicolour banding and electronic mapping resources
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Gisselsson, David
- Abstract
Acquired chromosome abnormalities in tumours often reflect pathogenetic events at the gene level. Multicolour fluorescence in situhybridisation (FISH) with single-copy probes offers extensive possibilities to characterise chromosome breakpoints in relation to the physical map of the human genome. This approach is based on the construction of comprehensive EST-based maps, combinatorial labelling of probes, and tumour cell preparations optimised for metaphase FISH. Information from several electronically available databases is combined into an integrated physical map, to which clones carrying yeast and bacterial artificial chromosomes are anchored. Extracted DNA or PCR products from these clones are then fluorescently labelled by one or several fluors, allowing simultaneous FISH detection of multiple loci. To improve hybridisation efficiency and reduce background fluorescence, standard methods for chromosome preparation from cultured tumour cells are complemented with a prolonged trypsin treatment to obtain complete disaggregation of cells, and exposure of the metaphase spreads to detergent and saline at high temperature, followed by pepsin digestion to remove extracellular matrix and cytoplasmic debris. The resulting colour-banding allows the characterisation of chromosome abnormalities in relation to expressed sequences, even in tumours exhibiting highly complex rearrangements.
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- 2001
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22. Abnormal Nuclear Shape in Solid Tumors Reflects Mitotic Instability
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Gisselsson, David, Björk, Jonas, Höglund, Mattias, Mertens, Fredrik, Dal Cin, Paola, Åkerman, Måns, and Mandahl, Nils
- Abstract
Abnormalities in nuclear morphology are frequently observed in malignant tissues but the mechanisms behind these phenomena are still poorly understood. In this study, the relation between abnormal nuclear shape and chromosomal instability was explored in short-term tumor cell cultures. Mitotically unstable ring and dicentric chromosomes were identified by fluorescence in situhybridization at metaphase and subsequently localized in interphase nuclei from five malignant soft tissue tumors. The vast majority (71 to 86%) of nuclear blebs, chromatin strings, and micronuclei contained material from the unstable chromosomes, whereas few (<11%) were positive for stable chromosomes. Nuclear morphology was also evaluated in fibroblasts and an osteosarcoma cell line exposed to irradiation. A linear correlation was found between the frequency of abnormalities in nuclear shape, on one hand, and cells with unstable chromosomes (r= 0.87) and anaphase bridge configurations (r= 0.98), on the other hand. The relation between nuclear shape and karyotypic pattern was investigated further in cultures from 58 tumors of bone, soft tissue, and epithelium. Blebs, strings, and micronuclei were significantly more frequent in tumors that contained rings, dicentrics, or telomeric associations than in those exhibiting only stable aberrations (P< 0.001) and a positive correlation (r= 0.78) was found between the frequency of such nuclear abnormalities and the intratumor heterogeneity of structural chromosome aberrations. These results indicate that the formation of nuclear blebs, chromatin strings, and micronuclei in malignant tissues is closely related to the breakage-fusion-bridge type of mitotic disturbances. Abnormalities in nuclear shape may thus primarily be regarded as an indicator of genetic instability and intratumor heterogeneity, independent of cytogenetic complexity and the grade of malignancy.
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- 2001
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23. Cytogenetics of hepatoblastoma: Further characterization of 1q rearrangements by fluorescence in situ hybridization: An international collaborative study
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Parada, Luis Antonio, Limon, Janusz, Iliszko, Mariola, Czauderna, Piotr, Gisselsson, David, Höglund, Mattias, Kullendorff, Carl-Magnus, Wiebe, Thomas, Mertens, Fredrik, and Johansson, Bertil
- Abstract
Hepatoblastoma (HBT) is the most common hepatic neoplasm in children. This notwithstanding, little is known about pathogenetic factors, such as genetic abnormalities, of importance for the development and progression of this tumor type. To date, only 33 cytogenetically abnormal HBT have been published, and trisomies for chromosomes 2 and 20 have been shown to be the most frequent aberrations. Recently, unbalanced translocations involving proximal 1q have been described in several HBT, suggesting that a pathogenetically important gene maps to 1q. Six primary and one recurrent HBT were cytogenetically analyzed after short-term tissue culture. In addition, fluorescence in situ hybridization (FISH) studies, using locus-specific probes, were performed on three of these pediatric HBT as well as on one previously reported adult HBT. Total or partial trisomy 8, gain of chromosome 20, and structural rearrangements of chromosome 1 were detected in three HBT, and overrepresentation of chromosome 2 material was found in two HBT. The adjacent chromosome bands 1q12 and 1q21 were involved in three translocations, t(1;2), t(1;4), and t(1;11), which were all unbalanced and resulted in gain of 1q material. The previously reported adult HBT displayed 1q deletions with breakpoints at 1q12-21. FISH analyses of the 1q rearrangements revealed that all breakpoints were within the heterochromatic region. These findings provide further support for the importance of trisomies 2, 8, and 20 and rearrangements of 1q in the development of HBT. Furthermore, the consistent localization of breakpoints within the heterochromatic segment of chromosome 1 suggests that the important pathogenetic consequence of 1q abnormalities is the resulting genomic imbalance rather than a specific gene rearrangement. Med. Pediatr. Oncol. 34:165170, 2000. © 2000 Wiley-Liss, Inc.
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- 2000
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24. Anti-tumor effects of rigosertib in high-risk neuroblastoma
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Radke, Katarzyna, Hansson, Karin, Sjölund, Jonas, Wolska, Magdalena, Karlsson, Jenny, Esfandyari, Javanshir, Pietras, Kristian, Aaltonen, Kristina, Gisselsson, David, and Bexell, Daniel
- Abstract
•Analysis of multiple tumor types reveal neuroblastoma sensitivity to rigosertib.•Neuroblastoma 2D and 3D organoid models are sensitive to rigosertib.•Rigosertib causes G2M cell cycle arrest rather than inhibition of Ras binding domains.•Rigosertib prolongs survival of MYCN- amplified patient-derived xenograft tumors.•Combination of rigosertib and vincristine is synergistic against neuroblastoma.
- Published
- 2021
- Full Text
- View/download PDF
25. Variable stability of chromosomes containing amplified α-satellite sequences in human mesenchymal tumours
- Author
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Gisselsson, David, Höglund, Mattias, Mertens, Fredrik, and Mandahl, Nils
- Abstract
Abstract.: Alpha-satellite sequences are found in the centromeric region of all human chromosomes and have been implicated in centromeric function. We describe the structure and behaviour of chromosomes containing amplified human alphoid DNA from chromosome 12, in an osteosarcoma cell line (OSA) and an atypical lipomatous tumour (ALT). In OSA, the amplified material was detected in one large marker chromosome, whereas in ALT amplified sequences were observed in chromosomes of variable number and appearance. The marker in OSA was mitotically stable, but those in ALT exhibited a high degree of mitotic instability, forming bridges at anaphase and chromatin strings between interphase nuclei. The amplified α-satellite arrays reacted positively with human anti-centromeric antiserum and anti-centromere protein B antibodies in both tumours. Centromere protein C, previously shown to be present only in functional kinetochores, was invariably detected at the constriction of the marker in OSA, while one-fifth of markers in ALT appeared to exhibit additional centromere protein C-positive regions outside the primary constriction, indicating that the observed chromosomal instability in ALT might, at least in part, be a consequence of the occasional formation of more than one functional kinetochore. In OSA the alphoid DNA was coamplified with unique sequences from central 12q and the amplified material was C-band negative but in ALT amplified material from central 12q as well as sequences from proximal 12p were detected, resulting in C-band-positive areas. A propensity for additional kinetochore formation might thus be associated with the coamplification of alphoid DNA and pericentromeric sequences from chromosome 12.
- Published
- 1999
- Full Text
- View/download PDF
26. Hibernomas are Characterized by Homozygous Deletions in the Multiple Endocrine Neoplasia Type I Region
- Author
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Gisselsson, David, Höglund, Mattias, Mertens, Fredrik, Dal Cin, Paola, and Mandahl, Nils
- Abstract
Hibernomas are benign tumors of brown fat, frequently characterized by aberrations of chromosome band 11q13. In this study, the chromosome 11 changes in five hibernomas were analyzed in detail by metaphase fluorescence in situ. hybridization. In all cases, complex rearrangements leading to loss of chromosome 11 material were found. Deletions were present not only in those chromosomes that were shown to be rearranged by G-banding, but in four cases also in the ostensibly normal homologues, resulting in homozygous loss of several loci. Among these, the gene for multiple endocrine neoplasia type I (MEN1) was most frequently deleted. In addition to the MEN1deletions, heterozygous loss of a second region, approximately 3 Mb distal to MEN1, was found in all five cases, adding to previous evidence for a second tumor suppressor locus in 11q13.
- Published
- 1999
- Full Text
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27. Aneuploidy in cancer: Sudden or sequential?
- Author
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Gisselsson, David
- Abstract
Comment on: Gisselsson D, et al. Proc Natl Acad Sci USA 2010; 107:20489-93.
- Published
- 2011
- Full Text
- View/download PDF
28. Therapeutic targeting of KSP in preclinical models of high-risk neuroblastoma
- Author
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Hansson, Karin, Radke, Katarzyna, Aaltonen, Kristina, Saarela, Jani, Mañas, Adriana, Sjölund, Jonas, Smith, Emma M., Pietras, Kristian, Påhlman, Sven, Wennerberg, Krister, Gisselsson, David, and Bexell, Daniel
- Abstract
KSP inhibition results in cell death through mitotic arrest and causes regression of neuroblastoma PDX tumors in mice.
- Published
- 2020
- Full Text
- View/download PDF
29. Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome
- Author
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Chen, Yin-Huai, Grigelioniene, Giedre, Newton, Phillip T., Gullander, Jacob, Elfving, Maria, Hammarsjö, Anna, Batkovskyte, Dominyka, Alsaif, Hessa S., Kurdi, Wesam I.Y., Abdulwahab, Firdous, Shanmugasundaram, Veerabahu, Devey, Luke, Bacrot, Séverine, Brodszki, Jana, Huber, Celine, Hamel, Ben, Gisselsson, David, Papadogiannakis, Nikos, Jedrycha, Katarina, Gürtl-Lackner, Barbara, Chagin, Andrei S., Nishimura, Gen, Aschenbrenner, Dominik, Alkuraya, Fowzan S., Laurence, Arian, Cormier-Daire, Valérie, and Uhlig, Holm H.
- Abstract
The gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines. Previous studies have identified cytokine-selective IL6ST defects that preserve LIF signaling. We describe three unrelated families with at least five affected individuals who presented with lethal Stüve-Wiedemann–like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping). Functional tests showed absent cellular responses to GP130-dependent cytokines including IL-6, IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF). Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect. This study identifies a new genetic syndrome caused by the complete lack of signaling of a whole family of GP130-dependent cytokines in humans and highlights the importance of the LIF signaling pathway in pre- and perinatal development.
- Published
- 2020
- Full Text
- View/download PDF
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