11 results on '"Doris Steinemann"'
Search Results
2. Relapses and treatment-related events contributed equally to poor prognosis in children with ABL-class fusion positive B-cell acute lymphoblastic leukemia treated according to AIEOP-BFM protocols
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Gunnar Cario, Veronica Leoni, Valentino Conter, Andishe Attarbaschi, Marketa Zaliova, Lucie Sramkova, Gianni Cazzaniga, Grazia Fazio, Rosemary Sutton, Sarah Elitzur, Shai Izraeli, Melchior Lauten, Franco Locatelli, Giuseppe Basso, Barbara Buldini, Anke K. Bergmann, Jana Lentes, Doris Steinemann, Gudrun Göhring, Brigitte Schlegelberger, Oskar A. Haas, Denis Schewe, Swantje Buchmann, Anja Moericke, Deborah White, Tamas Revesz, Martin Stanulla, Georg Mann, Nicole Bodmer, Nira Arad-Cohen, Jan Zuna, Maria Grazia Valsecchi, Martin Zimmermann, Martin Schrappe, and Andrea Biondi
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
ABL-class fusions other than BCR-ABL1 characterize around 2–3% of precursor B-cell acute lymphoblastic leukemia. Case series indicated that patients suffering from these subtypes have a dismal outcome and may benefit from the introduction of tyrosine kinase inhibitors. We analyzed clinical characteristics and outcome of 46 ABL-class fusion positive cases other than BCR-ABL1 treated according to AIEOP-BFM (Associazione Italiana di Ematologia-Oncologia Pediatrica-Berlin-Frankfurt-Münster) ALL 2000 and 2009 protocols; 13 of them received a tyrosine kinase inhibitor (TKI) during different phases of treatment. ABL-class fusion positive cases had a poor early treatment response: minimal residual disease levels of ≥5×10−4 were observed in 71.4% of patients after induction treatment and in 51.2% after consolidation phase. For the entire cohort of 46 cases, the 5-year probability of event-free survival was 49.1+8.9% and that of overall survival 69.6+7.8%; the cumulative incidence of relapse was 25.6+8.2% and treatment-related mortality (TRM) 20.8+6.8%. One out of 13 cases with TKI added to chemotherapy relapsed while eight of 33 cases without TKI treatment suffered from relapse, including six in 17 patients who had not received hematopoietic stem cell transplantation. Stem cell transplantation seems to be effective in preventing relapses (only three relapses in 25 patients), but was associated with a very high TRM (6 patients). These data indicate a major need for an early identification of ABL-class fusion positive acute lymphoblastic leukemia cases and to establish a properly designed, controlled study aimed at investigating the use of TKI, the appropriate chemotherapy backbone and the role of hematopoietic stem cell transplantation. (Registered at: clinicaltrials.gov identifier: NTC00430118, NCT00613457, NCT01117441).
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- 2020
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3. MDS1 and EVI1 complex locus (MECOM): a novel candidate gene for hereditary hematological malignancies
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Tim Ripperger, Winfried Hofmann, Jan C. Koch, Katayoon Shirneshan, Detlef Haase, Gerald Wulf, Peter R. Issing, Matthias Karnebogen, Gunnar Schmidt, Bernd Auber, Brigitte Schlegelberger, Thomas Illig, Birgit Zirn, and Doris Steinemann
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2018
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4. Managing individuals with propensity to myeloid malignancies due to germline RUNX1 deficiency
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Tim Ripperger, Marcel Tauscher, Detlef Haase, Frank Griesinger, Brigitte Schlegelberger, and Doris Steinemann
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2011
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5. Mutations in the let-7 binding site - a mechanism of RAS activation in juvenile myelomonocytic leukemia?
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Doris Steinemann, Marcel Tauscher, Inka Praulich, Charlotte M. Niemeyer, Christian Flotho, and Brigitte Schlegelberger
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2010
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6. Mitotic recombination and compound-heterozygous mutations are predominant NF1-inactivating mechanisms in children with juvenile myelomonocytic leukemia and neurofibromatosis type 1
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Doris Steinemann, Larissa Arning, Inka Praulich, Manfred Stuhrmann, Henrik Hasle, Jan Starý, Brigitte Schlegelberger, Charlotte M. Niemeyer, and Christian Flotho
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Children with neurofibromatosis type 1 (NF-1), being constitutionally deficient for one allele of the NF1 gene, are at greatly increased risk of juvenile myelomonocytic leukemia (JMML). NF1 is a negative regulator of RAS pathway activity, which has a central role in JMML. To further clarify the role of biallelic NF1 gene inactivation in the pathogenesis of JMML, we investigated the somatic NF1 lesion in 10 samples from children with JMML/NF-1. We report that two-thirds of somatic events involved loss of heterozygosity (LOH) at the NF1 locus, predominantly caused by segmental uniparental disomy of large parts of chromosome arm 17q. One-third of leukemias showed compound-heterozygous NF1-inactivating mutations. A minority of cases exhibited somatic interstitial deletions. The findings reinforce the emerging role of somatic mitotic recombination as a leukemogenic mechanism. In addition, they support the concept that biallelic NF1 inactivation in hematopoietic progenitor cells is required for transformation to JMML in children with NF-1.
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- 2010
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7. Promoter methylation of PARG1, a novel candidate tumor suppressor gene in mantle cell lymphomas
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Tim Ripperger, Nils von Neuhoff, Kathrin Kamphues, Makito Emura, Ulrich Lehmann, Marcel Tauscher, Margit Schraders, Patricia Groenen, Britta Skawran, Cornelia Rudolph, Evelyne Callet-Bauchu, Johan H.J.M. van Krieken, Brigitte Schlegelberger, and Doris Steinemann
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background and Objectives Mantle cell lymphoma (MCL), a mature B-cell neoplasm, is genetically characterized by the translocation t(11;14)(q13;q32). However, secondary alterations are required for malignant transformation. The identification of inactivated tumor suppressor genes contributing to the development of MCL may lead to further elucidation of the biology of this disease and help to identify novel targets for therapy.Design and Methods Whole genome microarray-based gene expression profiling on treated versus untreated MCL cell lines was used to identify genes induced by 5-aza-2′-deoxycytidine. The degree of promoter methylation and transcriptional silencing of selected genes was then proven in MCL cell lines and primary cases by methylation-specific polymerase chain reaction (PCR) techniques, real-time PCR and gene expression profiling.Results After 5-aza-2′-deoxycytidine treatment, we identified more than 1000 upregulated genes, 16 of which were upregulated ≥3-fold. Most of them were not known to be silenced by methylation in MCL. A low expression of ING1, RUNX3 and BNIP3L was observed in three of the five the MCL cell lines. In addition, the expression of PARG1, which is located in the frequently deleted region 1p22.1, was substantially reduced and displayed at least partial promoter methylation in all investigated MCL cell lines as well as in 31 primary MCL cases.Interpretation and Conclusions In summary, we identified interesting novel candidate genes that probably contribute to the progression of MCL and suggest that PARG1 is a strong candidate tumor suppressor gene in MCL.
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- 2007
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8. Promoter methylation of PARG1, a novel candidate tumor suppressor gene in mantle-cell lymphomas
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Marcel Tauscher, Tim Ripperger, Britta Skawran, Evelyne Callet-Bauchu, Makito Emura, Kathrin Kamphues, Margit Schraders, Ulrich Lehmann, Doris Steinemann, Cornelia Rudolph, Nils von Neuhoff, Patricia J. T. A. Groenen, Brigitte Schlegelberger, and Johan H. J. M. van Krieken
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Candidate gene ,Age-related aspects of cancer [ONCOL 2] ,Genetics and epigenetic pathways of disease [NCMLS 6] ,Transcription, Genetic ,Tumor suppressor gene ,Lymphoma, Mantle-Cell ,Neuroinformatics [DCN 3] ,Biology ,Decitabine ,Polymerase Chain Reaction ,Translocation, Genetic ,Translational research [ONCOL 3] ,Cell Line, Tumor ,hemic and lymphatic diseases ,Gene expression ,Perception and Action [DCN 1] ,Humans ,Gene silencing ,Genes, Tumor Suppressor ,Gene Silencing ,Epigenetics ,Promoter Regions, Genetic ,neoplasms ,Molecular diagnosis, prognosis and monitoring [UMCN 1.2] ,Oligonucleotide Array Sequence Analysis ,Chromosomes, Human, Pair 14 ,Hereditary cancer and cancer-related syndromes [ONCOL 1] ,Chromosomes, Human, Pair 11 ,Gene Expression Profiling ,GTPase-Activating Proteins ,DNA, Neoplasm ,Hematology ,Methylation ,DNA Methylation ,Molecular biology ,Candidate Tumor Suppressor Gene ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,Gene expression profiling ,Chromosomes, Human, Pair 1 ,Azacitidine ,Disease Progression ,Functional Neurogenomics [DCN 2] - Abstract
Contains fulltext : 53271.pdf (Publisher’s version ) (Open Access) BACKGROUND AND OBJECTIVES: Mantle cell lymphoma (MCL), a mature B-cell neoplasm, is genetically characterized by the translocation t(11;14)(q13;q32). However, secondary alterations are required for malignant transformation. The identification of inactivated tumor suppressor genes contributing to the development of MCL may lead to further elucidation of the biology of this disease and help to identify novel targets for therapy. DESIGN AND METHODS: Whole genome microarray-based gene expression profiling on treated versus untreated MCL cell lines was used to identify genes induced by 5-aza-2'-deoxycytidine. The degree of promoter methylation and transcriptional silencing of selected genes was then proven in MCL cell lines and primary cases by methylation-specific polymerase chain reaction (PCR) techniques, real-time PCR and gene expression profiling. RESULTS: After 5-aza-2'-deoxycytidine treatment, we identified more than 1000 upregulated genes, 16 of which were upregulated > or =3-fold. Most of them were not known to be silenced by methylation in MCL. A low expression of ING1, RUNX3 and BNIP3L was observed in three of the five the MCL cell lines. In addition, the expression of PARG1, which is located in the frequently deleted region 1p22.1, was substantially reduced and displayed at least partial promoter methylation in all investigated MCL cell lines as well as in 31 primary MCL cases. INTERPRETATION AND CONCLUSIONS: In summary, we identified interesting novel candidate genes that probably contribute to the progression of MCL and suggest that PARG1 is a strong candidate tumor suppressor gene in MCL.
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- 2007
9. Managing individuals with propensity to myeloid malignancies due to germline RUNX1 deficiency
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Brigitte Schlegelberger, Tim Ripperger, Detlef Haase, Marcel Tauscher, Doris Steinemann, and Frank Griesinger
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Chromosome 7 (human) ,Myeloid ,Myelodysplastic syndromes ,Platelet disorder ,Review Article ,Hematology ,Biology ,medicine.disease ,Bioinformatics ,Germline ,Telomere ,chemistry.chemical_compound ,medicine.anatomical_structure ,RUNX1 ,chemistry ,Myelodysplastic Syndromes ,hemic and lymphatic diseases ,Immunology ,medicine ,Humans - Abstract
Familial cases of myelodysplastic syndromes are rare, but are immensely valuable for the investigation of the molecular pathogenesis of myelodysplasia in general. The best-characterized familial myelodysplastic syndrome is that of familial platelet disorder with propensity to myeloid malignancy, caused by heterozygous germline RUNX1 mutations. Recently, there has been an increase in the number of reported cases, allowing for better understanding of the incidence, clinical features, and pathogenesis of this disorder. These recent cases have highlighted the clinical variability of the disorder and confirmed that many patients lack a bleeding and/or thrombocytopenia history. Additionally, several cases of T-acute lymphoblastic leukemia have now been reported, confirming a risk of lymphoid leukemia in patients with inherited RUNX1 mutations. Furthermore, an increased awareness of clinicians has helped detect a number of additional families affected by inherited myelodysplastic syndromes, resulting in the identification of novel causative mechanisms of disease, such as RUNX1 deficiency resulting from constitutional microdeletions of 21q22 and myelodysplasia-associated with telomerase deficiency. Awareness of predisposition to myelodysplastic syndromes and acute myeloid leukemia in families may be of critical importance in the management of younger patients with myelodysplasia in whom allogeneic hematopoietic stem cell transplantation is considered. Such families should be investigated for inherited deficiencies of RUNX1 and/or telomerase to prevent the use of an affected sibling as a donor for transplantation. Here we provide an update on familial platelet disorder in addition to a review of other known familial myelodysplastic syndromes.
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- 2011
10. Gene-expression profiles and their association with drug resistance in adult acute myeloid leukemia
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Michael, Heuser, Luzie U, Wingen, Doris, Steinemann, Gunnar, Cario, Nils, von Neuhoff, Marcel, Tauscher, Lars, Bullinger, Juergen, Krauter, Gerhard, Heil, Hartmut, Döhner, Brigitte, Schlegelberger, and Arnold, Ganser
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Adult ,Genetic Markers ,Male ,Adolescent ,Gene Expression Profiling ,Antineoplastic Agents ,Middle Aged ,Survival Analysis ,Leukemia, Myeloid, Acute ,Drug Resistance, Neoplasm ,Humans ,Female ,Aged ,Oligonucleotide Array Sequence Analysis - Abstract
From 20-50% of patients with acute myeloid leukemia (AML) are primarily resistant to induction chemotherapy. It has previously been shown that resistance to the first cycle of induction chemotherapy is an independent prognostic factor. We investigated whether resistance to chemotherapy be represented by gene-expression profiles, and which genes are associated with resistance.cDNA microarrays containing approximately 41,000 features were used to compare the gene-expression profile of AML blasts between 33 patients with good or poor response to induction chemotherapy. Data generated by cDNA-arrays were confirmed by quantitative reverse transcription polymerase chain reaction.Using significance analysis of microarrays, we identified a characteristic gene-expression profile which distinguished AML samples from patients with good or poor responses. In hierarchical clustering analysis poor responders clustered together with normal CD34+ cells. Moreover, 13/40 (32.5%) genes highly expressed in poor responders are also overexpressed in hematopoietic stem/progenitor cells. Prediction analysis using 10-fold cross-validation revealed an 80% overall accuracy. Using the treatment-response signature to predict the outcome in an independent test set of 104 AML patients, samples were separated into two subgroups with significantly inferior response rate (43.5% vs. 66.7%, p=0.04), significantly shorter event-free and overall survival (p=0.01 and p=0.03, respectively) in the poor-response compared to in the good-response signature group. In multivariate analysis, the treatment-response signature was an independent prognostic factor (hazard ratio, 2.1, 95% confidence interval 1.2 to 3.6, p=0.006).Resistance to chemotherapy in AML can be identified by gene-expression profiling before treatment and seems to be mediated by a transcriptional program active in hematopoietic stem/progenitor cells.
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- 2005
11. Mutations in the let-7 binding site - a mechanism of RAS activation in juvenile myelomonocytic leukemia?
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Marcel Tauscher, Christian Flotho, Inka Praulich, Doris Steinemann, Brigitte Schlegelberger, and Charlotte M. Niemeyer
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Neuroblastoma RAS viral oncogene homolog ,Genetics ,CDC25A ,Mutation ,Binding Sites ,Juvenile myelomonocytic leukemia ,Hematology ,Biology ,medicine.disease_cause ,medicine.disease ,Up-Regulation ,PTPN11 ,MicroRNAs ,HMGA2 ,Leukemia, Myelomonocytic, Juvenile ,ras Proteins ,Cancer research ,medicine ,biology.protein ,Humans ,KRAS ,Cyclin-dependent kinase 6 ,Letter to the Editor - Abstract
Juvenile myelomonocytic leukemia (JMML) is a rare hematologic malignancy in childhood and accounts for less than 3% of all childhood hematologic malignancies. 1 The role of hyperactive RAS in JMML is underlined by the fact that approximately 80% of JMML develop due to gain-of-function mutations in NRAS, KRAS, PTPN11 and SOS1 or homozygous loss-of-function mutations in NF1 or c-CBL. 2-4 These genes are all components of the RAS/ERK signaling network, implicating deregulation of this signaling pathway in JMML pathogenesis. Therefore, it may be speculated that JMML lacking known mutations of genes playing a role in RAS signaling may carry other mutations, which result in activation of this pathway. Recently, germline mi-RNA gene variations were pro posed to affect the expression levels of tumor suppressor or oncogenes and, thereby, familial/hereditary cancer risk. 5 The let-7 mi-RNA family targets many important genes including cell cycle regulators such as CDC25A and CDK6, a number of early embryonic genes including HMGA2, Mlin-41 and IMP-1 and promoters of growth including RAS and C-MYC. In Caenorhabditis elegans let7 mutant seam cells fail to exit the cell cycle and to terminally differentiate, thus demonstrating continuous prolif eration, a hallmark of cancer. 6 Human RAS expression was also shown to be regulated by let-7. 7 Evidence of a role of let-7 in cancer came from the observation that lung tumor tissues display significantly reduced let-7 levels and significantly increased RAS protein levels relative to nor mal lung tissue. 8
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- 2010
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