Vera Binder
University of Düsseldorf
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by Vera Binder.
The Lancet | 2008
Dani Bercovich; Ithamar Ganmore; Linda M. Scott; Gilad Wainreb; Yehudit Birger; Arava Elimelech; Chen Shochat; Giovanni Cazzaniga; Andrea Biondi; Giuseppe Basso; Gunnar Cario; Martin Schrappe; Martin Stanulla; Sabine Strehl; Oskar A. Haas; Georg Mann; Vera Binder; Arndt Borkhardt; Helena Kempski; Jan Trka; Bella Bielorei; Smadar Avigad; Batia Stark; Owen P. Smith; Nicole Dastugue; Jean Pierre Bourquin; Nir Ben Tal; Anthony R. Green; Shai Izraeli
BACKGROUND Children with Downs syndrome have a greatly increased risk of acute megakaryoblastic and acute lymphoblastic leukaemias. Acute megakaryoblastic leukaemia in Downs syndrome is characterised by a somatic mutation in GATA1. Constitutive activation of the JAK/STAT (Janus kinase and signal transducer and activator of transcription) pathway occurs in several haematopoietic malignant diseases. We tested the hypothesis that mutations in JAK2 might be a common molecular event in acute lymphoblastic leukaemia associated with Downs syndrome. METHODS JAK2 DNA mutational analysis was done on diagnostic bone marrow samples obtained from 88 patients with Downs syndrome-associated acute lymphoblastic leukaemia; and 216 patients with sporadic acute lymphoblastic leukaemia, Downs syndrome-associated acute megakaryoblastic leukaemia, and essential thrombocythaemia. Functional consequences of identified mutations were studied in mouse haematopoietic progenitor cells. FINDINGS Somatically acquired JAK2 mutations were identified in 16 (18%) patients with Downs syndrome-associated acute lymphoblastic leukaemia. The only patient with non-Downs syndrome-associated leukaemia but with a JAK2 mutation had an isochromosome 21q. Children with a JAK2 mutation were younger (mean [SE] age 4.5 years [0.86] vs 8.6 years [0.59], p<0.0001) at diagnosis. Five mutant alleles were identified, each affecting a highly conserved arginine residue (R683). These mutations immortalised primary mouse haematopoietic progenitor cells in vitro, and caused constitutive Jak/Stat activation and cytokine-independent growth of BaF3 cells, which was sensitive to pharmacological inhibition with JAK inhibitor I. In modelling studies of the JAK2 pseudokinase domain, R683 was situated in an exposed conserved region separated from the one implicated in myeloproliferative disorders. INTERPRETATION A specific genotype-phenotype association exists between the type of somatic mutation within the JAK2 pseudokinase domain and the development of B-lymphoid or myeloid neoplasms. Somatically acquired R683 JAK2 mutations define a distinct acute lymphoblastic leukaemia subgroup that is uniquely associated with trisomy 21. JAK2 inhibitors could be useful for treatment of this leukaemia. FUNDING Israel Trade Ministry, Israel Science Ministry, Jewish National Fund UK, Sam Waxman Cancer Research Foundation, Israel Science Foundation, Israel Cancer Association, Curtis Katz, Constantiner Institute for Molecular Genetics, German-Israel Foundation, and European Commission FP6 Integrated Project EUROHEAR.
Genes, Chromosomes and Cancer | 2013
Cai Chen; Christoph Bartenhagen; Michael Gombert; Vera Okpanyi; Vera Binder; Silja Röttgers; Jutta Bradtke; Andrea Teigler-Schlegel; Jochen Harbott; Sebastian Ginzel; Ralf Thiele; Ute Fischer; Martin Dugas; Jianda Hu; Arndt Borkhardt
Near haploidy (23–29 chromosomes) is a numerical cytogenetic aberration in childhood acute lymphoblastic leukemia (ALL) associated with particularly poor outcome. In contrast, high hyperdiploidy (51–67 chromosomes) has a favorable prognosis. Correct classification and appropriate risk stratification of near haploidy is frequently hampered by the presence of apparently high hyperdiploid clones that arise by endoreduplication of the original near haploid clone. We evaluated next‐generation‐sequencing (NGS) to distinguish between “high hyperdiploid” leukemic clones of near haploid and true high hyperdiploid origin. Five high hyperdiploid ALL cases and the “high hyperdiploid” cell line MHH‐CALL‐2, derived from a near haploid clone, were tested for uniparental isodisomy. NGS showed that all disomic chromosomes of MHH‐CALL‐2, but none of the patients, were of uniparental origin, thus reliably discriminating these subtypes. Whole‐exome‐ and whole‐genome‐sequencing of MHH‐CALL‐2 revealed homozygous non‐synonymous coding mutations predicted to be deleterious for the protein function of 63 genes, among them known cancer‐associated genes, such as FANCA, NF1, TCF7L2, CARD11, EP400, histone demethylases, and transferases (KDM6B, KDM1A, PRDM11). Only eight of these were also, but heterozygously, mutated in the high hyperdiploid patients. Structural variations in MHH‐CALL‐2 include a homozygous deletion (MTAP/CDKN2A/CDKN2B/ANRIL), a homozygous inversion (NCKAP5), and an unbalanced translocation (FAM189A1). Together, the sequence variations provide MHH‐CALL‐2 with capabilities typically acquired during cancer development, e.g., loss of cell cycle control, enhanced proliferation, lack of DNA repair, cell death evasion, and disturbance of epigenetic gene regulation. Poorer prognosis of near haploid ALL most likely results from full penetrance of a large array of detrimental homozygous mutations.
Leukemia Research | 2015
Cai Chen; Christoph Bartenhagen; Michael Gombert; Vera Okpanyi; Vera Binder; Silja Röttgers; Jutta Bradtke; Andrea Teigler-Schlegel; Jochen Harbott; Sebastian Ginzel; Ralf Thiele; Peter Husemann; Pina Fanny Ida Krell; Arndt Borkhardt; Martin Dugas; Jianda Hu; Ute Fischer
20% of children suffering from high hyperdiploid acute lymphoblastic leukemia develop recurrent disease. The molecular mechanisms are largely unknown. Here, we analyzed the genetic landscape of five patients at relapse, who developed recurrent disease without prior high-risk indication using whole-exome- and whole-genome-sequencing. Oncogenic mutations of RAS pathway genes (NRAS, KRAS, FLT3, n=4) and deactivating mutations of major epigenetic regulators (CREBBP, EP300, each n=2 and ARID4B, EZH2, MACROD2, MLL2, each n=1) were prominent in these cases and virtually absent in non-recurrent cases (n=6) or other pediatric acute lymphoblastic leukemia cases (n=18). In relapse nucleotide variations were detected in cell fate determining transcription factors (GLIS1, AKNA). Structural genomic alterations affected genes regulating B-cell development (IKZF1, PBX1, RUNX1). Eleven novel translocations involved the genes ART4, C12orf60, MACROD2, TBL1XR1, LRRN4, KIAA1467, and ELMO1/MIR1200. Typically, patients harbored only single structural variations, except for one patient who displayed massive rearrangements in the context of a germline tumor suppressor TP53 mutation and a Li-Fraumeni syndrome-like family history. Another patient harbored a germline mutation in the DNA repair factor ATM. In summary, the relapse patients of our cohort were characterized by somatic mutations affecting the RAS pathway, epigenetic and developmental programs and germline mutations in DNA repair pathways.
Human Mutation | 2014
Vera Binder; Christoph Bartenhagen; Vera Okpanyi; Michael Gombert; Birte Moehlendick; Bianca Behrens; Hans-Ulrich Klein; Harald Rieder; Pina Fanny Ida Krell; Martin Dugas; Nikolas H. Stoecklein; Arndt Borkhardt
Unbiased amplification of the whole‐genome amplification (WGA) of single cells is crucial to study cancer evolution and genetic heterogeneity, but is challenging due to the high complexity of the human genome. Here, we present a new workflow combining an efficient adapter‐linker PCR‐based WGA method with second‐generation sequencing. This approach allows comparison of single cells at base pair resolution. Amplification recovered up to 74% of the human genome. Copy‐number variants and loss of heterozygosity detected in single cell genomes showed concordance of up to 99% to pooled genomic DNA. Allele frequencies of mutations could be determined accurately due to an allele dropout rate of only 2%, clearly demonstrating the low bias of our PCR‐based WGA approach. Sequencing with paired‐end reads allowed genome‐wide analysis of structural variants. By direct comparison to other WGA methods, we further endorse its suitability to analyze genetic heterogeneity.
PLOS ONE | 2015
Miriam Schulz; Darja Karpova; Gabriele Spohn; Annette Damert; Erhard Seifried; Vera Binder; Halvard-Björn Bönig
The genetics responsible for the inter-individually variable G-CSF responsiveness remain elusive. A single nucleotide polymorphism (SNP) in the 3’UTR of CXCL12, rs1801157, was implicated in X4-tropic HiV susceptibility and later, in two small studies, in G-CSR responsiveness in patients and donors. The position of the SNP in the 3’UTR together with in-silico predictions suggested differential binding of micro-RNA941 as an underlying mechanism. In a cohort of 515 healthy stem cell donors we attempted to reproduce the correlation of the CXCL12 3’UTR SNP and mobilization responses and tested the role of miR941 in this context. The SNP was distributed with the expected frequency. Mobilization efficiency for CD34+ cells in WT, heterozygous and homozygous SNP individuals was indistinguishable, even after controlling for gender. miR941 expression in non-hematopoietic bone marrow cells was undetectable and miR941 did not interact with the 3’ UTR of CXCL12. Proposed effects of the SNP rs1801157 on G-CSF responsiveness cannot be confirmed in a larger cohort.
Journal of Clinical Immunology | 2012
Sujal Ghosh; Friedhelm R. Schuster; Vera Binder; Tim Niehues; Stephan Baldus; Peter Seiffert; Hans-Jürgen Laws; Arndt Borkhardt; Roland Meisel
Blood | 2007
Ithamar Ganmore; Dan Bercovich; Linda M. Scott; Anthony R. Green; Giovanni Cazzaniga; Andrea Biondi; Giuseppe Basso; Gunnar Cario; Martin Schrappe; Martin Stanulla; Sabine Strehl; Oskar A. Haas; Vera Binder; Arndt Borkhardt; Jan Trka; Bella Bielorei; Smadar Avigad; Batia Stark; Jean-Pierre Bourquin; Owen P. Smith; Helena Kempski; Shai Izraeli
Blood | 2013
Cai Chen; Christoph Bartenhagen; Michael Gombert; Vera Okpanyi; Vera Binder; Andrea Teigler-Schlegel; Jutta Bradtke; Silja Roettgers; Jochen Harbott; Sebastian Ginzel; Ralf Thiele; Martin Dugas; Jianda Hu; Arndt Borkhardt
Blood | 2012
Vera Okpanyi; Christoph Bartenhagen; Michael Gombert; Sebastian Ginzel; Pina Fanny Ida Krell; Peter Husemann; Cai Chen; Vera Binder; Jutta Bradtke; Andrea Teigler-Schlegel; Silja Roettgers; Jochen Harbott; Martin Stanulla; Cornelia Eckert; Ralf Thiele; Martin Dugas; Arndt Borkhardt; Ute Fischer
Blood | 2011
Cai Chen; Christoph Bartenhagen; Michael Gombert; Vera Okpanyi; Vera Binder; Silja Roettgers; Jutta Bradtke; Andrea Teigler-Schlegel; Ute Fischer; Jochen Harbott; Jianda Hu; Martin Dugas; Arndt Borkhardt