10 results on '"Morten Tulstrup"'
Search Results
2. TET2 mutations are associated with hypermethylation at key regulatory enhancers in normal and malignant hematopoiesis
- Author
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Morten Tulstrup, Mette Soerensen, Jakob Werner Hansen, Linn Gillberg, Maria Needhamsen, Katja Kaastrup, Kristian Helin, Kaare Christensen, Joachim Weischenfeldt, and Kirsten Grønbæk
- Subjects
Science - Abstract
TET2 mutations are frequent in myeloid malignancies and in elderly individuals with or without cytopenia. Here, the authors analyse the association between TET2 mutations and methylation changes in healthy elderly twins and patients with cytopenia and compare them to those from leukemia.
- Published
- 2021
- Full Text
- View/download PDF
3. Clonal Hematopoiesis and Epigenetic Age Acceleration in Elderly Danish Twins
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Mette Soerensen, Morten Tulstrup, Jakob Werner Hansen, Joachim Weischenfeldt, Kirsten Grønbæk, and Kaare Christensen
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) is common in the elderly and has been reported to associate with accelerated epigenetic age (AgeAccel), especially intrinsic (ie, cell-type independent) AgeAccel and to a lesser degree extrinsic AgeAccel, which reflects the immune-cell composition of the peripheral blood. We investigated the association between CHIP occurrence and AgeAccel in 154 Danish twin pairs aged 73–90 years (mean 79), using both individual-level and intrapair analyses, the latter to control for shared genetic and environmental factors. Of 308 individuals, 116 carried a CHIP mutation. CHIP carriers had non-significantly increased AgeAccel compared with non-carriers; the strongest association was for the Intrinsic Epigenetic Age Acceleration (IEAA) estimator (CHIP carriers 1.4 years older, P = 0.052). In intrapair analyses, the extrinsic Hannum age estimator showed the strongest association (1.6 years older, P = 0.027). In mutation-specific analyses, TET2 mutations were associated with the extrinsic Hannum age estimator in both individual-level (3.0 years older, P = 0.003) and intrapair analyses (2.8 years older, P = 0.05). DNMT3A mutations were associated with IEAA in individual-level (1.9 years older, P = 0.034) but not intrapair analysis (0.9 years, P = 0.41). Analyses of logit-transformed variant allele frequency were generally consistent with these results. Together, these observations indicate that different factors may be driving the expansion of DNMT3A and TET2 clones, respectively. Finally, CHIP carriers accelerated in both the Hannum and the GrimAge age estimators did not have an increased mortality risk in our cohort followed for 22 years (HR = 1.02, P = 0.93), hence not replicating the stratification model proposed by Nachun et al.
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- 2022
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4. Acute and persistent symptoms in non-hospitalized PCR-confirmed COVID-19 patients
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Sofie Bliddal, Karina Banasik, Ole Birger Pedersen, Janna Nissen, Lisa Cantwell, Michael Schwinn, Morten Tulstrup, David Westergaard, Henrik Ullum, Søren Brunak, Niels Tommerup, Bjarke Feenstra, Frank Geller, Sisse Rye Ostrowski, Kirsten Grønbæk, Claus Henrik Nielsen, Susanne Dam Nielsen, and Ulla Feldt-Rasmussen
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Medicine ,Science - Abstract
Abstract Reports of persistent symptoms after hospitalization with COVID-19 have raised concern of a “long COVID” syndrome. This study aimed at determining the prevalence of and risk factors for acute and persistent symptoms in non-hospitalized patients with polymerase chain reaction (PCR) confirmed COVID-19. We conducted a cohort study of non-hospitalized participants identified via the Danish Civil Registration System with a SARS-CoV-2-positive PCR-test and available biobank samples. Participants received a digital questionnaire on demographics and COVID-19-related symptoms. Persistent symptoms: symptoms > 4 weeks (in sensitivity analyses > 12 weeks). We included 445 participants, of whom 34% were asymptomatic. Most common acute symptoms were fatigue, headache, and sneezing, while fatigue and reduced smell and taste were most severe. Persistent symptoms, most commonly fatigue and memory and concentration difficulties, were reported by 36% of 198 symptomatic participants with follow-up > 4 weeks. Risk factors for persistent symptoms included female sex (women 44% vs. men 24%, odds ratio 2.7, 95% CI 1.4–5.1, p = 0.003) and BMI (odds ratio 1.1, 95% CI 1.0–1.2, p = 0.001). In conclusion, among non-hospitalized PCR-confirmed COVID-19 patients one third were asymptomatic while one third of symptomatic participants had persistent symptoms illustrating the heterogeneity of disease presentation. These findings should be considered in health care planning and policy making related to COVID-19.
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- 2021
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5. Trypsin-encoding PRSS1-PRSS2 variations influence the risk of asparaginase-associated pancreatitis in children with acute lymphoblastic leukemia: a Ponte di Legno toxicity working group report
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Benjamin O. Wolthers, Thomas L. Frandsen, Chirag J. Patel, Rachid Abaji, Andishe Attarbaschi, Shlomit Barzilai, Antonella Colombini, Gabriele Escherich, Marie Grosjean, Maja Krajinovic, Eric Larsen, Der-Cherng Liang, Anja Möricke, Kirsten K. Rasmussen, Sujith Samarasinghe, Lewis B. Silverman, Inge M. van der Sluis, Martin Stanulla, Morten Tulstrup, Rachita Yadav, Wenjian Yang, Ester Zapotocka, Ramneek Gupta, and Kjeld Schmiegelow
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Asparaginase-associated pancreatitis is a life-threatening toxicity to childhood acute lymphoblastic leukemia treatment. To elucidate genetic predisposition and asparaginase-associated pancreatitis pathogenesis, ten trial groups contributed remission samples from patients aged 1.0−17.9 years treated for acute lymphoblastic leukemia between 2000 and 2016. Cases (n=244) were defined by the presence of at least two of the following criteria: (i) abdominal pain; (ii) levels of pancreatic enzymes ≥3 × upper normal limit; and (iii) imaging compatible with pancreatitis. Controls (n=1320) completed intended asparaginase therapy, with 78% receiving ≥8 injections of pegylated-asparaginase, without developing asparaginase-associated pancreatitis. rs62228256 on 20q13.2 showed the strongest association with the development of asparaginase-associated pancreatitis (odds ratio=3.75; P=5.2×10−8). Moreover, rs13228878 (OR=0.61; P=7.1×10−6) and rs10273639 (OR=0.62; P=1.1×10−5) on 7q34 showed significant association with the risk of asparaginase-associated pancreatitis. A Dana Farber Cancer Institute ALL Consortium cohort consisting of patients treated on protocols between 1987 and 2004 (controls=285, cases=33), and the Children’s Oncology Group AALL0232 cohort (controls=2653, cases=76) were available as replication cohorts for the 20q13.2 and 7q34 variants, respectively. While rs62228256 was not validated as a risk factor (P=0.77), both rs13228878 (P=0.03) and rs10273639 (P=0.04) were. rs13228878 and rs10273639 are in high linkage disequilibrium (r2=0.94) and associated with elevated expression of the PRSS1 gene, which encodes for trypsinogen, and are known risk variants for alcohol-associated and sporadic pancreatitis in adults. Intra-pancreatic trypsinogen cleavage to proteolytic trypsin induces autodigestion and pancreatitis. In conclusion, this study finds a shared genetic predisposition between asparaginase-associated pancreatitis and non-asparaginase-associated pancreatitis, and targeting the trypsinogen activation pathway may enable identification of effective interventions for asparaginase-associated pancreatitis.
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- 2019
- Full Text
- View/download PDF
6. Impact of U2AF1 mutations on circular RNA expression in myelodysplastic neoplasms
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Eileen Wedge, Ulvi Ahmadov, Thomas B. Hansen, Zongliang Gao, Morten Tulstrup, Christophe Côme, Sridhar Nonavinkere Srivatsan, Tanzir Ahmed, Jakob S. Jespersen, Balthasar C. Schlotmann, Claudia Schöllkopf, Klas Raaschou-Jensen, Niels Ødum, Jørgen Kjems, Rasmus O. Bak, Matthew J. Walter, Kirsten Grønbæk, and Lasse S. Kristensen
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Cancer Research ,Mice ,Splicing Factor U2AF/genetics ,Oncology ,Doxycycline ,Neoplasms ,RNA Splicing ,RNA, Circular/genetics ,Mutation ,Animals ,Hematology ,RNA Splicing Factors/genetics ,Myelodysplastic Syndromes/genetics - Abstract
Mutations in U2AF1 are relatively common in myelodysplastic neoplasms (MDS) and are associated with an inferior prognosis, but the molecular mechanisms underlying this are not fully elucidated. Circular RNAs (circRNAs) have been implicated in cancer, but it is unknown how mutations in splicing factors may impact on circRNA biogenesis. Here, we used RNA-sequencing to investigate the effects of U2AF1 mutations on circRNA expression in K562 cells with a doxycycline-inducible U2AF1 S34 mutation, in a mouse model with a doxycycline-inducible U2AF1 S34 mutation, and in FACS-sorted CD34+ bone marrow cells from MDS patients with either U2AF1 S34 or U2AF1 Q157 mutations. In all contexts, we found an increase in global circRNA levels in the U2AF1-mutated setting, which was independent of expression changes in the cognate linear host genes. In patients, the U2AF1 S34 and U2AF1 Q157 mutations were both associated with an overall increased expression of circRNAs. circRNAs generated by a non-Alu-mediated mechanism generally showed the largest increase in expression levels. Several well-described cancer-associated circRNAs, including circZNF609 and circCSNK1G3, were upregulated in MDS patients with U2AF1 mutations compared to U2AF1-wildtype MDS controls. In conclusion, high circRNA expression is observed in association with U2AF1 mutations in three biological systems, presenting an interesting possibility for biomarker and therapeutic investigation.
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- 2023
7. TET2 mutations are associated with hypermethylation at key regulatory enhancers in normal and malignant hematopoiesis
- Author
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Maria Needhamsen, Jakob Werner Hansen, Morten Tulstrup, Mette Soerensen, Kaare Christensen, Katja Kaastrup, Kristian Helin, Kirsten Grønbæk, Joachim Weischenfeldt, and Linn Gillberg
- Subjects
Epigenomics ,Myeloid ,health care facilities, manpower, and services ,Science ,General Physics and Astronomy ,Biology ,Peripheral blood mononuclear cell ,General Biochemistry, Genetics and Molecular Biology ,Article ,Acute myeloid leukaemia ,DNA Methyltransferase 3A ,Dioxygenases ,hemic and lymphatic diseases ,medicine ,Humans ,DNA (Cytosine-5-)-Methyltransferases ,Enhancer ,Transcription factor ,Cancer genetics ,Cytopenia ,Multidisciplinary ,Myeloproliferative Disorders ,General Chemistry ,social sciences ,DNA Methylation ,medicine.disease ,Hematopoietic Stem Cells ,humanities ,Hematopoiesis ,DNA-Binding Proteins ,Haematopoiesis ,medicine.anatomical_structure ,Enhancer Elements, Genetic ,Risk factors ,DNA methylation ,Mutation ,Cancer research ,Stem cell ,Haematological diseases ,Transcription Factors - Abstract
Mutations in the epigenetic modifier TET2 are frequent in myeloid malignancies and clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS). Here, we investigate associations between TET2 mutations and DNA methylation in whole blood in 305 elderly twins, 15 patients with CCUS and 18 healthy controls. We find that TET2 mutations are associated with DNA hypermethylation at enhancer sites in whole blood in CHIP and in both granulocytes and mononuclear cells in CCUS. These hypermethylated sites are associated with leukocyte function and immune response and ETS-related and C/EBP-related transcription factor motifs. While the majority of TET2-associated hypermethylation sites are shared between CHIP and in AML, we find a set of AML-specific hypermethylated loci at active enhancer elements in hematopoietic stem cells. In summary, we show that TET2 mutations is associated with hypermethylated enhancers involved in myeloid differentiation in both CHIP, CCUS and AML patients., TET2 mutations are frequent in myeloid malignancies and in elderly individuals with or without cytopenia. Here, the authors analyse the association between TET2 mutations and methylation changes in healthy elderly twins and patients with cytopenia and compare them to those from leukemia.
- Published
- 2021
8. Trypsin-encoding PRSS1-PRSS2 variations influence the risk of asparaginase-associated pancreatitis in children with acute lymphoblastic leukemia: a Ponte di Legno toxicity working group report
- Author
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Lewis B. Silverman, Marie Grosjean, Chirag J. Patel, Wenjian Yang, Morten Tulstrup, Benjamin Ole Wolthers, Rachita Yadav, Eric Larsen, Kjeld Schmiegelow, Thomas Frandsen, Ramneek Gupta, Rachid Abaji, Inge M. van der Sluis, Anja Möricke, Sujith Samarasinghe, Maja Krajinovic, Der-Cherng Liang, Antonella Colombini, Andishe Attarbaschi, Shlomit Barzilai, Gabriele Escherich, Kirsten K. Rasmussen, Martin Stanulla, and Ester Zapotocka
- Subjects
Male ,medicine.medical_specialty ,Asparaginase ,Adolescent ,Genotype ,Trypsinogen ,Antineoplastic Agents ,Gastroenterology ,Models, Biological ,Polymorphism, Single Nucleotide ,Article ,Polyethylene Glycols ,chemistry.chemical_compound ,SDG 3 - Good Health and Well-being ,Internal medicine ,medicine ,Genetic predisposition ,PRSS2 ,Humans ,Genetic Predisposition to Disease ,Trypsin ,Trypsinogen activation ,Child ,Childhood Acute Lymphoblastic Leukemia ,Alleles ,Genetic Association Studies ,business.industry ,Genetic Variation ,Infant ,Hematology ,Odds ratio ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Acute Lymphoblastic Leukemia ,Phenotype ,chemistry ,Pancreatitis ,Child, Preschool ,Female ,business - Abstract
Asparaginase-associated pancreatitis is a life-threatening toxicity to childhood acute lymphoblastic leukemia treatment. To elucidate genetic predisposition and asparaginase-associated pancreatitis pathogenesis, ten trial groups contributed remission samples from patients aged 1.0−17.9 years treated for acute lymphoblastic leukemia between 2000 and 2016. Cases (n=244) were defined by the presence of at least two of the following criteria: (i) abdominal pain; (ii) levels of pancreatic enzymes ≥3 x upper normal limit; and (iii) imaging compatible with pancreatitis. Controls (n=1320) completed intended asparaginase therapy, with 78% receiving ≥8 injections of pegylated-asparaginase, without developing asparaginase-associated pancreatitis. rs62228256 on 20q13.2 showed the strongest association with the development of asparaginase-associated pancreatitis (odds ratio=3.75; P=5.2x10 -8 ). Moreover, rs13228878 (OR=0.61; P=7.1x10 -6 ) and rs10273639 (OR=0.62; P=1.1x10 -5 ) on 7q34 showed significant association with the risk of asparaginase-associated pancreatitis. A Dana Farber Cancer Institute ALL Consortium cohort consisting of patients treated on protocols between 1987 and 2004 (controls=285, cases=33), and the Children’s Oncology Group AALL0232 cohort (controls=2653, cases=76) were available as replication cohorts for the 20q13.2 and 7q34 variants, respectively. While rs62228256 was not validated as a risk factor (P=0.77), both rs13228878 (P=0.03) and rs10273639 (P=0.04) were. rs13228878 and rs10273639 are in high linkage disequilibrium (r 2 =0.94) and associated with elevated expression of the PRSS1 gene, which encodes for trypsinogen, and are known risk variants for alcohol-associated and sporadic pancreatitis in adults. Intra-pancreatic trypsinogen cleavage to proteolytic trypsin induces autodigestion and pancreatitis. In conclusion, this study finds a shared genetic predisposition between asparaginase-associated pancreatitis and non-asparaginase-associated pancreatitis, and targeting the trypsinogen activation pathway may enable identification of effective interventions for asparaginase-associated pancreatitis.
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- 2019
9. Genetic predisposition to PEG-asparaginase hypersensitivity in children treated according to NOPHO ALL2008
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Ramneek Gupta, Goda Vaitkeviciene, Louise Tram Henriksen, Arja Harila-Saari, Jonas Abrahamsson, Sofie Gottschalk Højfeldt, Mats Heyman, Olafur G. Jonsson, Birgitte Klug Albertsen, Benjamin Ole Wolthers, Päivi M. Lähteenmäki, Kjeld Schmiegelow, Bendik Lund, Kaie Pruunsild, and Morten Tulstrup
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Male ,Allergy ,Asparaginase ,Adolescent ,Genome-wide association study ,Human leukocyte antigen ,PEG-asparaginase ,Polyethylene Glycols ,Drug Hypersensitivity ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,ATP Binding Cassette Transporter, Subfamily B, Member 3 ,HLA-DQ Antigens ,Antineoplastic Combined Chemotherapy Protocols ,Genetic predisposition ,Medicine ,Humans ,Genetic Predisposition to Disease ,Child ,genome-wide association study ,biology ,business.industry ,Genetic Variation ,Infant ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,ta3123 ,Enzyme assay ,Neoplasm Proteins ,paediatric acute lymphoblastic leukaemia ,chemistry ,030220 oncology & carcinogenesis ,Child, Preschool ,Immunology ,Toxicity ,biology.protein ,TAP2 ,Chromosomes, Human, Pair 6 ,Female ,hypersensitivity ,business ,Chromosomes, Human, Pair 19 ,030215 immunology ,Genome-Wide Association Study ,Transcription Factors - Abstract
Asparaginase is essential in childhood acute lymphoblastic leukaemia (ALL) treatment, however hypersensitivity reactions to pegylated asparaginase (PEG-asparaginase) hampers anti-neoplastic efficacy. Patients with PEG-asparaginase hypersensitivity have been shown to possess zero asparaginase enzyme activity. Using this measurement to define the phenotype, we investigated genetic predisposition to PEG-asparaginase hypersensitivity in a genome-wide association study (GWAS). From July 2008 to March 2016, 1494 children were treated on the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol. Cases were defined by clinical hypersensitivity and no enzyme activity, controls had enzyme activity ≥ 100 iu/l and no hypersensitivity symptoms. PEG-asparaginase hypersensitivity was reported in 13·8% (206/1494) of patients. Fifty-nine cases and 772 controls fulfilled GWAS inclusion criteria. The CNOT3 variant rs73062673 on 19q13.42, was associated with PEG-asparaginase allergy (P = 4·68 × 10-8 ). We further identified two signals on chromosome 6 in relation to HLA-DQA1 (P = 9·37 × 10-6 ) and TAP2 (P = 1·59 × 10-5 ). This study associated variants in CNOT3 and in the human leucocyte antigen (HLA) region with PEG-asparaginase hypersensitivity, suggesting that not only genetic variations in the HLA region, but also regulation of these genes are of importance in the biology of this toxicity. Furthermore, our study emphasizes the importance of using asparaginase enzyme activity measurements to identify PEG-asparaginase hypersensitivity.
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- 2019
10. Individualized 6-mercaptopurine increments in consolidation treatment of childhood acute lymphoblastic leukemia:A NOPHO randomized controlled trial
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Olafur G. Jonsson, Mats Heyman, Jonas Abrahamsson, Bendik Lund, Kim Vettenranta, Hanne Vibeke Marquart, Birgitte Klug Albertsen, Thomas Frandsen, Kjeld Schmiegelow, and Morten Tulstrup
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0301 basic medicine ,Male ,medicine.medical_specialty ,Antimetabolites, Antineoplastic ,Neoplasm, Residual ,Lymphoblastic Leukemia ,acute lymphoblastic leukemia ,law.invention ,Consolidation therapy ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,children ,law ,Internal medicine ,Odds Ratio ,Medicine ,Humans ,6-mercaptopurine ,Child ,Childhood Acute Lymphoblastic Leukemia ,business.industry ,Mercaptopurine ,Hematology ,General Medicine ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Minimal residual disease ,Survival Analysis ,Surgery ,Blood Cell Count ,Consolidation Chemotherapy ,030104 developmental biology ,Treatment Outcome ,030220 oncology & carcinogenesis ,Child, Preschool ,Retreatment ,randomized controlled trial ,Female ,business ,consolidation therapy ,Standard therapy ,Biomarkers ,medicine.drug - Abstract
Objectives This randomized controlled trial tested the hypothesis that children with non-high risk acute lymphoblastic leukemia could benefit from individualized 6-mercaptopurine increments during consolidation therapy (NCT00816049). Primary and secondary end points were end of consolidation minimal residual disease (MRD) positivity and event-free survival. Methods 392 patients were randomized to experimental and 396 to standard therapy. Patients allocated to standard therapy received oral 6-mercaptopurine (25 mg/m2/day) from days 30 to 85, while the experimental arm received stepwise increments of additional 25 mg/m2/day beginning on days 50 and/or 71 unless dose-limiting myelosuppression had occurred. Results In the experimental arm, 166 patients (42%) received one dose increment, and 62 (16%) received two. 57 of 387 (15%) in the experimental arm were MRD positive at end of consolidation versus 77 of 389 (20%) in the control arm (P=0.08). Five-year probability of event-free survival was 0.89 (95% CI: 0.85–0.93) in the experimental arm versus 0.93 (0.90–0.96) in the control arm (P=0.13). The median accumulated length of 6-mercaptopurine treatment interruptions was 7 (IQR 2–12) in the experimental arm versus 4 (IQR 0–10) in the control arm (P=0.002). Conclusion This study found no benefit from individualized 6-mercaptopurine increments compared to standard therapy. This article is protected by copyright. All rights reserved.
- Published
- 2018
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