Publications

@article{pmid35145302,

title = {The genomic and spatial mobility of extrachromosomal DNA and its implications for cancer therapy},

author = {Eric van Leen and Lotte Brückner and Anton G Henssen},

doi = {10.1038/s41588-021-01000-z},

issn = {1546-1718},

year  = {2022},

date = {2022-02-01},

journal = {Nat Genet},

volume = {54},

number = {2},

pages = {107--114},

abstract = {Extrachromosomal DNA (ecDNA) amplification has been observed in at least 30 different cancer types and is associated with worse patient outcomes. This has been linked to increased oncogene dosage because both oncogenes and associated enhancers can occupy ecDNA. New data challenge the view that only oncogene dosage is affected by ecDNA, and raises the possibility that ecDNA could disrupt genome-wide gene expression. Recent investigations suggest that ecDNA localizes to specialized nuclear bodies (hubs) in which they can act in trans as ectopic enhancers for genes on other ecDNA or chromosomes. Moreover, ecDNA can reintegrate into the genome, possibly further disrupting the gene regulatory landscape in tumor cells. In this Perspective, we discuss the emerging properties of ecDNA and highlight promising avenues to exploit this new knowledge for the development of ecDNA-directed therapies for cancer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35711922,

title = {Detection and Validation of Circular DNA Fragments Using Nanopore Sequencing},

author = {Alicia Isabell Tüns and Till Hartmann and Simon Magin and Rocío Chamorro González and Anton George Henssen and Sven Rahmann and Alexander Schramm and Johannes Köster},

doi = {10.3389/fgene.2022.867018},

issn = {1664-8021},

year  = {2022},

date = {2022-01-01},

journal = {Front Genet},

volume = {13},

pages = {867018},

abstract = {Occurrence of extra-chromosomal circular DNA is a phenomenon frequently observed in tumor cells, and the presence of such DNA has been recognized as a marker of adverse outcome across cancer types. We here describe a computational workflow for identification of DNA circles from long-read sequencing data. The workflow is implemented based on the Snakemake workflow management system. Its key step uses a graph-theoretic approach to identify putative circular fragments validated on simulated reads. We then demonstrate robustness of our approach using nanopore sequencing of selectively enriched circular DNA by highly sensitive and specific recovery of plasmids and the mitochondrial genome, which is the only circular DNA in normal human cells. Finally, we show that the workflow facilitates detection of larger circular DNA fragments containing extrachromosomal copies of the MYCN oncogene and the respective breakpoints, which is a potentially useful application in disease monitoring of several cancer types.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34819668,

title = {ecDNA hubs drive cooperative intermolecular oncogene expression},

author = {King L Hung and Kathryn E Yost and Liangqi Xie and Quanming Shi and Konstantin Helmsauer and Jens Luebeck and Robert Schöpflin and Joshua T Lange and Rocío Chamorro González and Natasha E Weiser and Celine Chen and Maria E Valieva and Ivy Tsz-Lo Wong and Sihan Wu and Siavash R Dehkordi and Connor V Duffy and Katerina Kraft and Jun Tang and Julia A Belk and John C Rose and M Ryan Corces and Jeffrey M Granja and Rui Li and Utkrisht Rajkumar and Jordan Friedlein and Anindya Bagchi and Ansuman T Satpathy and Robert Tjian and Stefan Mundlos and Vineet Bafna and Anton G Henssen and Paul S Mischel and Zhe Liu and Howard Y Chang},

doi = {10.1038/s41586-021-04116-8},

issn = {1476-4687},

year  = {2021},

date = {2021-12-01},

journal = {Nature},

volume = {600},

number = {7890},

pages = {731--736},

abstract = {Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high expression of oncogenes through gene amplification and altered gene regulation. Gene induction typically involves cis-regulatory elements that contact and activate genes on the same chromosome. Here we show that ecDNA hubs-clusters of around 10-100 ecDNAs within the nucleus-enable intermolecular enhancer-gene interactions to promote oncogene overexpression. ecDNAs that encode multiple distinct oncogenes form hubs in diverse cancer cell types and primary tumours. Each ecDNA is more likely to transcribe the oncogene when spatially clustered with additional ecDNAs. ecDNA hubs are tethered by the bromodomain and extraterminal domain (BET) protein BRD4 in a MYC-amplified colorectal cancer cell line. The BET inhibitor JQ1 disperses ecDNA hubs and preferentially inhibits ecDNA-derived-oncogene transcription. The BRD4-bound PVT1 promoter is ectopically fused to MYC and duplicated in ecDNA, receiving promiscuous enhancer input to drive potent expression of MYC. Furthermore, the PVT1 promoter on an exogenous episome suffices to mediate gene activation in trans by ecDNA hubs in a JQ1-sensitive manner. Systematic silencing of ecDNA enhancers by CRISPR interference reveals intermolecular enhancer-gene activation among multiple oncogene loci that are amplified on distinct ecDNAs. Thus, protein-tethered ecDNA hubs enable intermolecular transcriptional regulation and may serve as units of oncogene function and cooperative evolution and as potential targets for cancer therapy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34272609,

title = {The effect of adjuvant therapies on long-term outcome for primary resected synovial sarcoma in a series of mainly children and adolescents},

author = {Monika Scheer and Christian Vokuhl and Sebastian Bauer and Jörg Fuchs and Steffan Loff and Beate Timmermann and Marc Münter and Anton George Henssen and Bernarda Kazanowska and Felix Niggli and Ruth Ladenstein and Gustaf Ljungman and Ewa Koscielniak and Thomas Klingebiel and },

doi = {10.1007/s00432-021-03614-6},

issn = {1432-1335},

year  = {2021},

date = {2021-12-01},

journal = {J Cancer Res Clin Oncol},

volume = {147},

number = {12},

pages = {3735--3747},

abstract = {BACKGROUND: The benefit of adjuvant therapy in synovial sarcoma (SS) treatment is under debate. Long-term follow-up data are missing.nnMETHODS: SS patients treated in the consecutive trials CWS-81, CWS-86, CWS-91, CWS-96, CWS-2002-P, and the SoTiSaR-registry till 2013 were analyzed.nnRESULTS: Median age of 185 patients was 13.9 years (0.1-56)-with median follow-up of 7.4 years for 163 survivors. Most tumors (76%) were located in extremities. Size was < 3 cm in 58 (31%), 3-5 cm in 59 (32%), 5-10 cm in 42 (23%), and > 10 cm in 13 (7%) (13 missing). In 84 (45%) tumors, first excision was complete (R0 corresponding to IRS-I-group) and in 101 (55%) marginal (R1 corresponding to IRS-II-group). In a subsequent surgical intervention during chemotherapy, R0-status was accomplished in 23 additional IRS-II-group patients with secondary surgery. Radiotherapy was administered to 135 (73%), thereof 62 with R0-status and 67 R1-status (6 missing information). Adjuvant chemotherapy was administered to all but six patients. 5-year event-free (EFS) and overall survival (OS) was 82.9% ± 5.7 (95%CI) and 92.5% ± 3.9. Local and metastatic relapse-free survival was 91.3% ± 4.3 and 92.3% ± 4.1 at 5 years, respectively. In the multivariate analysis, tumor size and no chemotherapy were independently associated with EFS. Size and site were associated with OS. In a detailed analysis of local and metastatic events, tumor size was associated with an independent risk for developing metastases. No independent factor for suffering local recurrence could be identified.nnDISCUSSION: Omission of chemotherapy in a non-stratified way seems not justified. Size governs survival due to high linear association with risk of suffering metastatic recurrence in a granular classification.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34815394,

title = {Spatial and temporal intratumour heterogeneity has potential consequences for single biopsy-based neuroblastoma treatment decisions},

author = {Karin Schmelz and Joern Toedling and Matt Huska and Maja C Cwikla and Louisa-Marie Kruetzfeldt and Jutta Proba and Peter F Ambros and Inge M Ambros and Sengül Boral and Marco Lodrini and Celine Y Chen and Martin Burkert and Dennis Guergen and Annabell Szymansky and Kathy Astrahantseff and Annette Kuenkele and Kerstin Haase and Matthias Fischer and Hedwig E Deubzer and Falk Hertwig and Patrick Hundsdoerfer and Anton G Henssen and Roland F Schwarz and Johannes H Schulte and Angelika Eggert},

doi = {10.1038/s41467-021-26870-z},

issn = {2041-1723},

year  = {2021},

date = {2021-11-01},

journal = {Nat Commun},

volume = {12},

number = {1},

pages = {6804},

abstract = {Intratumour heterogeneity is a major cause of treatment failure in cancer. We present in-depth analyses combining transcriptomic and genomic profiling with ultra-deep targeted sequencing of multiregional biopsies in 10 patients with neuroblastoma, a devastating childhood tumour. We observe high spatial and temporal heterogeneity in somatic mutations and somatic copy-number alterations which are reflected on the transcriptomic level. Mutations in some druggable target genes including ALK and FGFR1 are heterogeneous at diagnosis and/or relapse, raising the issue whether current target prioritization and molecular risk stratification procedures in single biopsies are sufficiently reliable for therapy decisions. The genetic heterogeneity in gene mutations and chromosome aberrations observed in deep analyses from patient courses suggest clonal evolution before treatment and under treatment pressure, and support early emergence of metastatic clones and ongoing chromosomal instability during disease evolution. We report continuous clonal evolution on mutational and copy number levels in neuroblastoma, and detail its implications for therapy selection, risk stratification and therapy resistance.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34771652,

title = {Inhibiting Lysine Demethylase 1A Improves L1CAM-Specific CAR T Cell Therapy by Unleashing Antigen-Independent Killing via the FAS-FASL Axis},

author = {Ornela Sulejmani and Laura Grunewald and Lena Andersch and Silke Schwiebert and Anika Klaus and Annika Winkler and Kathy Astrahantseff and Angelika Eggert and Anton G Henssen and Johannes H Schulte and Kathleen Anders and Annette Künkele},

doi = {10.3390/cancers13215489},

issn = {2072-6694},

year  = {2021},

date = {2021-10-01},

journal = {Cancers (Basel)},

volume = {13},

number = {21},

abstract = {Chimeric antigen receptor (CAR) T cell therapy has emerged as a promising treatment strategy, however, therapeutic success against solid tumors such as neuroblastoma remains modest. Recurrence of antigen-poor tumor variants often ultimately results in treatment failure. Using antigen-independent killing mechanisms such as the FAS receptor (FAS)-FAS ligand (FASL) axis through epigenetic manipulation may be a way to counteract the escape achieved by antigen downregulation. Analysis of public RNA-sequencing data from primary neuroblastomas revealed that a particular epigenetic modifier, the histone lysine demethylase 1A (KDM1A), correlated negatively with FAS expression. KDM1A is known to interact with TP53 to repress TP53-mediated transcriptional activation of genes, including . We showed that pharmacologically blocking KDM1A activity in neuroblastoma cells with the small molecule inhibitor, SP-2509, increased FAS cell-surface expression in a strictly TP53-dependent manner. FAS upregulation sensitized neuroblastoma cells to FAS-FASL-dependent killing and augmented L1CAM-directed CAR T cell therapy against antigen-poor or even antigen-negative tumor cells in vitro. The improved therapeutic response was abrogated when the FAS-FASL interaction was abolished with an antagonistic FAS antibody. Our results show that KDM1A inhibition unleashes an antigen-independent killing mechanism via the FAS-FASL axis to make tumor cell variants that partially or totally suppress antigen expression susceptible to CAR T cell therapy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34654445,

title = {Class I histone deacetylases (HDAC) critically contribute to Ewing sarcoma pathogenesis},

author = {Oxana Schmidt and Nadja Nehls and Carolin Prexler and Kristina von Heyking and Tanja Groll and Katharina Pardon and Heathcliff D Garcia and Tim Hensel and Dennis Gürgen and Anton G Henssen and Angelika Eggert and Katja Steiger and Stefan Burdach and Günther H S Richter},

doi = {10.1186/s13046-021-02125-z},

issn = {1756-9966},

year  = {2021},

date = {2021-10-01},

journal = {J Exp Clin Cancer Res},

volume = {40},

number = {1},

pages = {322},

abstract = {BACKGROUND: Histone acetylation and deacetylation seem processes involved in the pathogenesis of Ewing sarcoma (EwS). Here histone deacetylases (HDAC) class I were investigated.nnMETHODS: Their role was determined using different inhibitors including TSA, Romidepsin, Entinostat and PCI-34051 as well as CRISPR/Cas9 class I HDAC knockouts and HDAC RNAi. To analyze resulting changes microarray analysis, qRT-PCR, western blotting, Co-IP, proliferation, apoptosis, differentiation, invasion assays and xenograft-mouse models were used.nnRESULTS: Class I HDACs are constitutively expressed in EwS. Patients with high levels of individual class I HDAC expression show decreased overall survival. CRISPR/Cas9 class I HDAC knockout of individual HDACs such as HDAC1 and HDAC2 inhibited invasiveness, and blocked local tumor growth in xenograft mice. Microarray analysis demonstrated that treatment with individual HDAC inhibitors (HDACi) blocked an EWS-FLI1 specific expression profile, while Entinostat in addition suppressed metastasis relevant genes. EwS cells demonstrated increased susceptibility to treatment with chemotherapeutics including Doxorubicin in the presence of HDACi. Furthermore, HDACi treatment mimicked RNAi of EZH2 in EwS. Treated cells showed diminished growth capacity, but an increased endothelial as well as neuronal differentiation ability. HDACi synergizes with EED inhibitor (EEDi) in vitro and together inhibited tumor growth in xenograft mice. Co-IP experiments identified HDAC class I family members as part of a regulatory complex together with PRC2.nnCONCLUSIONS: Class I HDAC proteins seem to be important mediators of the pathognomonic EWS-ETS-mediated transcription program in EwS and in combination therapy, co-treatment with HDACi is an interesting new treatment opportunity for this malignant disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34187933,

title = {Negative correlation of single-cell  expression with tumorigenicity in rhabdomyosarcoma},

author = {Carla Regina and Ebrahem Hamed and Geoffroy Andrieux and Sina Angenendt and Michaela Schneider and Manching Ku and Marie Follo and Marco Wachtel and Eugene Ke and Ken Kikuchi and Anton G Henssen and Beat W Schäfer and Melanie Boerries and Amy J Wagers and Charles Keller and Simone Hettmer},

doi = {10.26508/lsa.202001002},

issn = {2575-1077},

year  = {2021},

date = {2021-09-01},

journal = {Life Sci Alliance},

volume = {4},

number = {9},

abstract = {Rhabdomyosarcomas (RMS) are phenotypically and functionally heterogeneous. Both primary human RMS cultures and low-passage  mouse RMS cell lines, which express the fusion oncoprotein Pax3:Foxo1 and lack the tumor suppressor  (), exhibit marked heterogeneity in  () expression at the single cell level. In mouse RMS cells,  expression is directed by the  promoter and coupled to  YFP/P3F mouse RMS cells included 87% G0/G1 cells and reorganized their actin cytoskeleton to produce a cellular phenotype characterized by more efficient adhesion and migration. This translated into higher tumor-propagating cell frequencies of YFP/P3F compared with YFP/P3F cells. Both YFP/P3F and YFP/P3F cells gave rise to mixed clones in vitro, consistent with fluctuations in  expression over time. Exposure to the anti-tropomyosin compound TR100 disrupted the cytoskeleton and reversed enhanced migration and adhesion of YFP/P3F RMS cells. Heterogeneous expression of  at the single cell level may provide a critical advantage during tumor progression.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34442335,

title = {Neuroblastoma Risk Assessment and Treatment Stratification with Hybrid Capture-Based Panel Sequencing},

author = {Annabell Szymansky and Louisa-Marie Kruetzfeldt and Lukas C Heukamp and Falk Hertwig and Jessica Theissen and Hedwig E Deubzer and Eva-Maria Willing and Roopika Menon and Steffen Fuchs and Theresa Thole and Stefanie Schulte and Karin Schmelz and Annette Künkele and Peter Lang and Jörg Fuchs and Angelika Eggert and Cornelia Eckert and Matthias Fischer and Anton G Henssen and Elias Rodriguez-Fos and Johannes H Schulte},

doi = {10.3390/jpm11080691},

issn = {2075-4426},

year  = {2021},

date = {2021-07-01},

journal = {J Pers Med},

volume = {11},

number = {8},

abstract = {For many years, the risk-based therapy stratification of children with neuroblastoma has relied on clinical and molecular covariates. In recent years, genome analysis has revealed further alterations defining risk, tumor biology, and therapeutic targets. The implementation of a robust and scalable method for analyzing traditional and new molecular markers in routine diagnostics is an urgent clinical need. Here, we investigated targeted panel sequencing as a diagnostic approach to analyze all relevant genomic neuroblastoma risk markers in one assay. Our "neuroblastoma hybrid capture sequencing panel" (NB-HCSP) assay employs a technology for the high-coverage sequencing (>1000×) of 55 selected genes and neuroblastoma-relevant genomic regions, which allows for the detection of single nucleotide changes, structural rearrangements, and copy number alterations. We validated our assay by analyzing 15 neuroblastoma cell lines and a cohort of 20 neuroblastomas, for which reference routine diagnostic data and genome sequencing data were available. We observed a high concordance for risk markers identified by the NB-HSCP assay, clinical routine diagnostics, and genome sequencing. Subsequently, we demonstrated clinical applicability of the NB-HCSP assay by analyzing routine clinical samples. We conclude that the NB-HCSP assay may be implemented into routine diagnostics as a single assay that covers all essential covariates for initial neuroblastoma classification, extended risk stratification, and targeted therapy selection.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33768209,

title = {Combined inhibition of Aurora-A and ATR kinase results in regression of -amplified neuroblastoma},

author = {Isabelle Roeschert and Evon Poon and Anton G Henssen and Heathcliff Dorado Garcia and Marco Gatti and Celeste Giansanti and Yann Jamin and Carsten P Ade and Peter Gallant and Christina Schülein-Völk and Petra Beli and Mark Richards and Mathias Rosenfeldt and Matthias Altmeyer and John Anderson and Angelika Eggert and Matthias Dobbelstein and Richard Bayliss and Louis Chesler and Gabriele Büchel and Martin Eilers},

doi = {10.1038/s43018-020-00171-8},

issn = {2662-1347},

year  = {2021},

date = {2021-03-01},

journal = {Nat Cancer},

volume = {2},

number = {3},

pages = {312--326},

abstract = {Amplification of  is the driving oncogene in a subset of high-risk neuroblastoma. The MYCN protein and the Aurora-A kinase form a complex during S phase that stabilizes MYCN. Here we show that MYCN activates Aurora-A on chromatin, which phosphorylates histone H3 at serine 10 in S phase, promotes the deposition of histone H3.3 and suppresses R-loop formation. Inhibition of Aurora-A induces transcription-replication conflicts and activates the Ataxia telangiectasia and Rad3 related (ATR) kinase, which limits double-strand break accumulation upon Aurora-A inhibition. Combined inhibition of Aurora-A and ATR induces rampant tumor-specific apoptosis and tumor regression in mouse models of neuroblastoma, leading to permanent eradication in a subset of mice. The therapeutic efficacy is due to both tumor cell-intrinsic and immune cell-mediated mechanisms. We propose that targeting the ability of Aurora-A to resolve transcription-replication conflicts is an effective therapy for -driven neuroblastoma (141 words).},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33801448,

title = {CD28 Co-Stimulus Achieves Superior CAR T Cell Effector Function against Solid Tumors Than 4-1BB Co-Stimulus},

author = {Ana Textor and Laura Grunewald and Kathleen Anders and Anika Klaus and Silke Schwiebert and Annika Winkler and Maria Stecklum and Jana Rolff and Anton G Henssen and Uta E Höpken and Angelika Eggert and Johannes H Schulte and Michael C Jensen and Thomas Blankenstein and Annette Künkele},

doi = {10.3390/cancers13051050},

issn = {2072-6694},

year  = {2021},

date = {2021-03-01},

journal = {Cancers (Basel)},

volume = {13},

number = {5},

abstract = {Spacer or co-stimulatory components in chimeric antigen receptor (CAR) design influence CAR T cell effector function. Few preclinical mouse models optimally support CAR candidate pre-selection for clinical development. Here we use a model in which murine CAR T cells can be exploited with human tumor xenografts. This mouse-in-mouse approach avoids limitations caused by species-specific factors crucial for CAR T cell survival, trafficking and function. We compared trafficking, expansion and tumor control for T cells expressing different CAR construct designs targeting two antigens (L1CAM or HER2), structurally identical except for spacer (long or short) or co-stimulatory (4-1BB or CD28) domains to be evaluated. Using monoclonal, murine-derived L1CAM-specific CAR T cells in Rag-/- mice harboring established xenografted tumors from a human neuroblastoma cell line revealed a clear superiority in CAR T cell trafficking using CD28 co-stimulation. L1CAM-targeting short spacer-CD28/ζ CAR T cells expanded the most at the tumor site and induced initial tumor regression. Treating patient-derived neuroblastoma xenografts with human L1CAM-targeting CAR T cells confirmed the superiority of CD28 co-stimulus. CD28 superiority was also demonstrated with HER2-specific CAR T cells (targeting ovarian carcinoma xenografts). Our findings encourage incorporating CD28 signaling into CAR design for adoptive T cell treatment of solid tumors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34267756,

title = {A Reproducible Bioprinted 3D Tumor Model Serves as a Preselection Tool for CAR T Cell Therapy Optimization},

author = {Laura Grunewald and Tobias Lam and Lena Andersch and Anika Klaus and Silke Schwiebert and Annika Winkler and Anton Gauert and Anja I Heeren-Hagemann and Kathy Astrahantseff and Filippos Klironomos and Alexander Thomas and Hedwig E Deubzer and Anton G Henssen and Angelika Eggert and Johannes H Schulte and Kathleen Anders and Lutz Kloke and Annette Künkele},

doi = {10.3389/fimmu.2021.689697},

issn = {1664-3224},

year  = {2021},

date = {2021-01-01},

journal = {Front Immunol},

volume = {12},

pages = {689697},

abstract = {Chimeric antigen receptor (CAR) T cell performance against solid tumors in mouse models and clinical trials is often less effective than predicted by CAR construct selection in two-dimensional (2D) cocultures. Three-dimensional (3D) solid tumor architecture is likely to be crucial for CAR T cell efficacy. We used a three-dimensional (3D) bioprinting approach for large-scale generation of highly reproducible 3D human tumor models for the test case, neuroblastoma, and compared these to 2D cocultures for evaluation of CAR T cells targeting the L1 cell adhesion molecule, L1CAM. CAR T cells infiltrated the model, and both CAR T and tumor cells were viable for long-term experiments and could be isolated as single-cell suspensions for whole-cell assays quantifying CAR T cell activation, effector function and tumor cell cytotoxicity. L1CAM-specific CAR T cell activation by neuroblastoma cells was stronger in the 3D model than in 2D cocultures, but neuroblastoma cell lysis was lower. The bioprinted 3D neuroblastoma model is highly reproducible and allows detection and quantification of CAR T cell tumor infiltration, representing a superior  analysis tool for preclinical CAR T cell characterization likely to better select CAR T cells for  performance than 2D cocultures.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33199677,

title = {Enhancer hijacking determines extrachromosomal circular MYCN amplicon architecture in neuroblastoma},

author = {Konstantin Helmsauer and Maria E Valieva and Salaheddine Ali and Rocío Chamorro González and Robert Schöpflin and Claudia Röefzaad and Yi Bei and Heathcliff Dorado Garcia and Elias Rodriguez-Fos and Montserrat Puiggròs and Katharina Kasack and Kerstin Haase and Csilla Keskeny and Celine Y Chen and Luis P Kuschel and Philipp Euskirchen and Verena Heinrich and Michael I Robson and Carolina Rosswog and Joern Toedling and Annabell Szymansky and Falk Hertwig and Matthias Fischer and David Torrents and Angelika Eggert and Johannes H Schulte and Stefan Mundlos and Anton G Henssen and Richard P Koche},

doi = {10.1038/s41467-020-19452-y},

issn = {2041-1723},

year  = {2020},

date = {2020-11-01},

journal = {Nat Commun},

volume = {11},

number = {1},

pages = {5823},

abstract = {MYCN amplification drives one in six cases of neuroblastoma. The supernumerary gene copies are commonly found on highly rearranged, extrachromosomal circular DNA (ecDNA). The exact amplicon structure has not been described thus far and the functional relevance of its rearrangements is unknown. Here, we analyze the MYCN amplicon structure using short-read and Nanopore sequencing and its chromatin landscape using ChIP-seq, ATAC-seq and Hi-C. This reveals two distinct classes of amplicons which explain the regulatory requirements for MYCN overexpression. The first class always co-amplifies a proximal enhancer driven by the noradrenergic core regulatory circuit (CRC). The second class of MYCN amplicons is characterized by high structural complexity, lacks key local enhancers, and instead contains distal chromosomal fragments harboring CRC-driven enhancers. Thus, ectopic enhancer hijacking can compensate for the loss of local gene regulatory elements and explains a large component of the structural diversity observed in MYCN amplification.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32807987,

title = {Extrachromosomal DNA is associated with oncogene amplification and poor outcome across multiple cancers},

author = {Hoon Kim and Nam-Phuong Nguyen and Kristen Turner and Sihan Wu and Amit D Gujar and Jens Luebeck and Jihe Liu and Viraj Deshpande and Utkrisht Rajkumar and Sandeep Namburi and Samirkumar B Amin and Eunhee Yi and Francesca Menghi and Johannes H Schulte and Anton G Henssen and Howard Y Chang and Christine R Beck and Paul S Mischel and Vineet Bafna and Roel G W Verhaak},

doi = {10.1038/s41588-020-0678-2},

issn = {1546-1718},

year  = {2020},

date = {2020-09-01},

journal = {Nat Genet},

volume = {52},

number = {9},

pages = {891--897},

abstract = {Extrachromosomal DNA (ecDNA) amplification promotes intratumoral genetic heterogeneity and accelerated tumor evolution; however, its frequency and clinical impact are unclear. Using computational analysis of whole-genome sequencing data from 3,212 cancer patients, we show that ecDNA amplification frequently occurs in most cancer types but not in blood or normal tissue. Oncogenes were highly enriched on amplified ecDNA, and the most common recurrent oncogene amplifications arose on ecDNA. EcDNA amplifications resulted in higher levels of oncogene transcription compared to copy number-matched linear DNA, coupled with enhanced chromatin accessibility, and more frequently resulted in transcript fusions. Patients whose cancers carried ecDNA had significantly shorter survival, even when controlled for tissue type, than patients whose cancers were not driven by ecDNA-based oncogene amplification. The results presented here demonstrate that ecDNA-based oncogene amplification is common in cancer, is different from chromosomal amplification and drives poor outcome for patients across many cancer types.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32333465,

title = {Central memory phenotype drives success of checkpoint inhibition in combination with CAR T cells},

author = {Karin Toews and Laura Grunewald and Silke Schwiebert and Anika Klaus and Annika Winkler and Solin Ali and Felix Zirngibl and Kathy Astrahantseff and Dimitrios L Wagner and Anton G Henssen and Hedwig E Deubzer and Johannes H Schulte and Sebastian Ochsenreither and Angelika Eggert and Annette Künkele},

doi = {10.1002/mc.23202},

issn = {1098-2744},

year  = {2020},

date = {2020-07-01},

journal = {Mol Carcinog},

volume = {59},

number = {7},

pages = {724--735},

abstract = {The immunosuppressive microenvironment in solid tumors is thought to form a barrier to the entry and efficacy of cell-based therapies such as chimeric antigen receptor (CAR) T cells. Combining CAR T cell therapy with checkpoint inhibitors has been demonstrated to oppose immune escape mechanisms in solid tumors and augment antitumor efficacy. We evaluated PD-1/PD-L1 signaling capacity and the impact of an inhibitor of this checkpoint axis in an in vitro system for cancer cell challenge, the coculture of L1CAM-specific CAR T cells with neuroblastoma cell lines. Fluorescence-activated cell sorting-based analyses and luciferase reporter assays were used to assess PD-1/PD-L1 expression on CAR T and tumor cells as well as CAR T cell ability to kill neuroblastoma cells. Coculturing neuroblastoma cell lines with L1CAM-CAR T cells upregulated PD-L1 expression on neuroblastoma cells, confirming adaptive immune resistance. Exposure to neuroblastoma cells also upregulated the expression of the PD-1/PD-L1 axis in CAR T cells. The checkpoint inhibitor, nivolumab, enhanced L1CAM-CAR T cell-directed killing. However, nivolumab-enhanced L1CAM-CAR T cell killing did not strictly correlate with PD-L1 expression on neuroblastoma cells. In fact, checkpoint inhibitor success relied on strong PD-1/PD-L1 axis expression in the CAR T cells, which in turn depended on costimulatory domains within the CAR construct, and more importantly, on the subset of T cells selected for CAR T cell generation. Thus, T cell subset selection for CAR T cell generation and CAR T cell prescreening for PD-1/PD-L1 expression could help determine when combination therapy with checkpoint inhibitors could improve treatment efficacy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32504042,

title = {Partner independent fusion gene detection by multiplexed CRISPR-Cas9 enrichment and long read nanopore sequencing},

author = {Christina Stangl and Sam de Blank and Ivo Renkens and Liset Westera and Tamara Verbeek and Jose Espejo Valle-Inclan and Rocio Chamorro González and Anton G Henssen and Markus J van Roosmalen and Ronald W Stam and Emile E Voest and Wigard P Kloosterman and Gijs van Haaften and Glen R Monroe},

doi = {10.1038/s41467-020-16641-7},

issn = {2041-1723},

year  = {2020},

date = {2020-06-01},

journal = {Nat Commun},

volume = {11},

number = {1},

pages = {2861},

abstract = {Fusion genes are hallmarks of various cancer types and important determinants for diagnosis, prognosis and treatment. Fusion gene partner choice and breakpoint-position promiscuity restricts diagnostic detection, even for known and recurrent configurations. Here, we develop FUDGE (FUsion Detection from Gene Enrichment) to accurately and impartially identify fusions. FUDGE couples target-selected and strand-specific CRISPR-Cas9 activity for fusion gene driver enrichment - without prior knowledge of fusion partner or breakpoint-location - to long read nanopore sequencing with the bioinformatics pipeline NanoFG. FUDGE has flexible target-loci choices and enables multiplexed enrichment for simultaneous analysis of several genes in multiple samples in one sequencing run. We observe on-average 665 fold breakpoint-site enrichment and identify nucleotide resolution fusion breakpoints within 2 days. The assay identifies cancer cell line and tumor sample fusions irrespective of partner gene or breakpoint-position. FUDGE is a rapid and versatile fusion detection assay for diagnostic pan-cancer fusion detection.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32415069,

title = {Oncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma},

author = {Aruna Marchetto and Shunya Ohmura and Martin F Orth and Maximilian M L Knott and Maria V Colombo and Chiara Arrigoni and Victor Bardinet and David Saucier and Fabienne S Wehweck and Jing Li and Stefanie Stein and Julia S Gerke and Michaela C Baldauf and Julian Musa and Marlene Dallmayer and Laura Romero-Pérez and Tilman L B Hölting and James F Amatruda and Andrea Cossarizza and Anton G Henssen and Thomas Kirchner and Matteo Moretti and Florencia Cidre-Aranaz and Giuseppina Sannino and Thomas G P Grünewald},

doi = {10.1038/s41467-020-16244-2},

issn = {2041-1723},

year  = {2020},

date = {2020-05-01},

journal = {Nat Commun},

volume = {11},

number = {1},

pages = {2423},

abstract = {Ewing sarcoma (EwS) is an aggressive childhood cancer likely originating from mesenchymal stem cells or osteo-chondrogenic progenitors. It is characterized by fusion oncoproteins involving EWSR1 and variable members of the ETS-family of transcription factors (in 85% FLI1). EWSR1-FLI1 can induce target genes by using GGAA-microsatellites as enhancers.Here, we show that EWSR1-FLI1 hijacks the developmental transcription factor SOX6 - a physiological driver of proliferation of osteo-chondrogenic progenitors - by binding to an intronic GGAA-microsatellite, which promotes EwS growth in vitro and in vivo. Through integration of transcriptome-profiling, published drug-screening data, and functional in vitro and in vivo experiments including 3D and PDX models, we discover that constitutively high SOX6 expression promotes elevated levels of oxidative stress that create a therapeutic vulnerability toward the oxidative stress-inducing drug Elesclomol.Collectively, our results exemplify how aberrant activation of a developmental transcription factor by a dominant oncogene can promote malignancy, but provide opportunities for targeted therapy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31932909,

title = {Synovial sarcoma disease characteristics and primary tumor sites differ between patient age groups: a report of the Cooperative Weichteilsarkom Studiengruppe (CWS)},

author = {Monika Scheer and Bernd Blank and Sebastian Bauer and Christian Vokuhl and Sabine Stegmaier and Simone Feuchtgruber and Anton Henssen and Monika Sparber-Sauer and Angelika Eggert and Ruppert Handgretinger and Arnulf Pekrun and Claudia Rossig and Stefan Rutkowski and Paul-Gerhardt Schlegel and Martin Schrappe and Thorsten Simon and Bernarda Kazanowska and Felix Niggli and Ruth Ladenstein and Gustaf Ljungman and Kirsi Jahnukainen and Jörg Fuchs and Stefan S Bielack and Ewa Koscielniak and Thomas Klingebiel and },

doi = {10.1007/s00432-019-03121-9},

issn = {1432-1335},

year  = {2020},

date = {2020-04-01},

journal = {J Cancer Res Clin Oncol},

volume = {146},

number = {4},

pages = {953--960},

abstract = {BACKGROUND: Older age is associated with worse outcome in synovial sarcoma (SS) patients. Differences in disease presentation among distinct age groups, however, are currently unknown.nnMETHODS: SS patients < 21 years registered in consecutive CWS trials over the period of 1981-2018 were evaluated. Characteristics were analyzed according to age groups using the Fisher's exact test.nnRESULTS: The study population included 432 SS patients. Disease characteristics differed according to age groups of children (0-12 years, n = 176), adolescents (13-16 years, n = 178), and young adults (17-21 years, n = 78). The proportion of invasive tumors (T2) was significantly higher in older patients: children 33%, adolescents 39% and young adults 54%, p = 0.009805. Similarly, the proportion of tumors > 10 cm was higher (13%, 21%, 31%; p = 0.005657) whereas conversely, the proportion of small tumors < 3 cm was lower in older patients (29%, 24%, 6%; p = 0.000104). The presence of metastases at first diagnosis was also highest in older patients (6%, 10%, 21%, p = 0.000963). Notably, the proportion of thigh tumors was higher in older patients (p = 0.04173), whereas the proportion of head-neck tumors was lower in older patients (p = 0.08896).nnCONCLUSIONS: The rates of large, invasive tumors and the presence of metastases are significantly associated with older patient age. Localization to the thigh is more frequent in older patients.nnDISCUSSION: The causes for these variations require further exploration.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32164354,

title = {High Specificity of BCL11B and GLG1 for EWSR1-FLI1 and EWSR1-ERG Positive Ewing Sarcoma},

author = {Martin F Orth and Tilman L B Hölting and Marlene Dallmayer and Fabienne S Wehweck and Tanja Paul and Julian Musa and Michaela C Baldauf and Didier Surdez and Olivier Delattre and Maximilian M L Knott and Laura Romero-Pérez and Merve Kasan and Florencia Cidre-Aranaz and Julia S Gerke and Shunya Ohmura and Jing Li and Aruna Marchetto and Anton G Henssen and Özlem Özen and Shintaro Sugita and Tadashi Hasegawa and Takayuki Kanaseki and Stefanie Bertram and Uta Dirksen and Wolfgang Hartmann and Thomas Kirchner and Thomas G P Grünewald},

doi = {10.3390/cancers12030644},

issn = {2072-6694},

year  = {2020},

date = {2020-03-01},

journal = {Cancers (Basel)},

volume = {12},

number = {3},

abstract = {Ewing sarcoma (EwS) is an aggressive cancer displaying an undifferentiated small-round-cell histomorphology that can be easily confused with a broad spectrum of differential diagnoses. Using comparative transcriptomics and immunohistochemistry (IHC), we previously identified BCL11B and GLG1 as potential specific auxiliary IHC markers for -positive EwS. Herein, we aimed at validating the specificity of both markers in a far larger and independent cohort of EwS (including -positive cases) and differential diagnoses. Furthermore, we evaluated their intra-tumoral expression heterogeneity. Thus, we stained tissue microarrays from 133 molecularly confirmed EwS cases and 320 samples from morphological mimics, as well as a series of patient-derived xenograft (PDX) models for BCL11B, GLG1, and CD99, and systematically assessed the immunoreactivity and optimal cut-offs for each marker. These analyses demonstrated that high BCL11B and/or GLG1 immunoreactivity in CD99-positive cases had a specificity of 97.5% and an accuracy of 87.4% for diagnosing EwS solely by IHC, and that the markers were expressed by -positive EwS. Only little intra-tumoral heterogeneity in immunoreactivity was observed for differential diagnoses. These results indicate that BCL11B and GLG1 may help as specific auxiliary IHC markers in diagnosing EwS in conjunction with CD99, especially if confirmatory molecular diagnostics are not available.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31304977,

title = {Reflection of neuroblastoma intratumor heterogeneity in the new OHC-NB1 disease model},

author = {Theresa M Thole and Joern Toedling and Annika Sprüssel and Sebastian Pfeil and Larissa Savelyeva and David Capper and Clemens Messerschmidt and Dieter Beule and Stefanie Groeneveld-Krentz and Cornelia Eckert and Guido Gambara and Anton G Henssen and Sabine Finkler and Johannes H Schulte and Anja Sieber and Nils Bluethgen and Christian R A Regenbrecht and Annette Künkele and Marco Lodrini and Angelika Eggert and Hedwig E Deubzer},

doi = {10.1002/ijc.32572},

issn = {1097-0215},

year  = {2020},

date = {2020-02-01},

journal = {Int J Cancer},

volume = {146},

number = {4},

pages = {1031--1041},

abstract = {Accurate modeling of intratumor heterogeneity presents a bottleneck against drug testing. Flexibility in a preclinical platform is also desirable to support assessment of different endpoints. We established the model system, OHC-NB1, from a bone marrow metastasis from a patient diagnosed with MYCN-amplified neuroblastoma and performed whole-exome sequencing on the source metastasis and the different models and passages during model development (monolayer cell line, 3D spheroid culture and subcutaneous xenograft tumors propagated in mice). OHC-NB1 harbors a MYCN amplification in double minutes, 1p deletion, 17q gain and diploid karyotype, which persisted in all models. A total of 80-540 single-nucleotide variants (SNVs) was detected in each sample, and comparisons between the source metastasis and models identified 34 of 80 somatic SNVs to be propagated in the models. Clonal reconstruction using the combined copy number and SNV data revealed marked clonal heterogeneity in the originating metastasis, with four clones being reflected in the model systems. The set of OHC-NB1 models represents 43% of somatic SNVs and 23% of the cellularity in the originating metastasis with varying clonal compositions, indicating that heterogeneity is partially preserved in our model system.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31869746,

title = {Small-Molecule Dual PLK1 and BRD4 Inhibitors are Active Against Preclinical Models of Pediatric Solid Tumors},

author = {Natalie Timme and Youjia Han and Shuai Liu and Hailemichael O Yosief and Heathcliff Dorado García and Yi Bei and Filippos Klironomos and Ian C MacArthur and Annabell Szymansky and Jennifer von Stebut and Victor Bardinet and Constantin Dohna and Annette Künkele and Jana Rolff and Patrick Hundsdörfer and Andrej Lissat and Georg Seifert and Angelika Eggert and Johannes H Schulte and Wei Zhang and Anton G Henssen},

doi = {10.1016/j.tranon.2019.09.013},

issn = {1936-5233},

year  = {2020},

date = {2020-02-01},

journal = {Transl Oncol},

volume = {13},

number = {2},

pages = {221--232},

abstract = {Simultaneous inhibition of multiple molecular targets is an established strategy to improve the continuance of clinical response to therapy. Here, we screened 49 molecules with dual nanomolar inhibitory activity against BRD4 and PLK1, best classified as dual kinase-bromodomain inhibitors, in pediatric tumor cell lines for their antitumor activity. We identified two candidate dual kinase-bromodomain inhibitors with strong and tumor-specific activity against neuroblastoma, medulloblastoma, and rhabdomyosarcoma tumor cells. Dual PLK1 and BRD4 inhibitor treatment suppressed proliferation and induced apoptosis in pediatric tumor cell lines at low nanomolar concentrations. This was associated with reduced MYCN-driven gene expression as assessed by RNA sequencing. Treatment of patient-derived xenografts with dual inhibitor UMB103 led to significant tumor regression. We demonstrate that concurrent inhibition of two central regulators of MYC protein family of protooncogenes, BRD4, and PLK1, with single small molecules has strong and specific antitumor effects in preclinical pediatric cancer models.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31844324,

title = {Extrachromosomal circular DNA drives oncogenic genome remodeling in neuroblastoma},

author = {Richard P Koche and Elias Rodriguez-Fos and Konstantin Helmsauer and Martin Burkert and Ian C MacArthur and Jesper Maag and Rocio Chamorro and Natalia Munoz-Perez and Montserrat Puiggròs and Heathcliff Dorado Garcia and Yi Bei and Claudia Röefzaad and Victor Bardinet and Annabell Szymansky and Annika Winkler and Theresa Thole and Natalie Timme and Katharina Kasack and Steffen Fuchs and Filippos Klironomos and Nina Thiessen and Eric Blanc and Karin Schmelz and Annette Künkele and Patrick Hundsdörfer and Carolina Rosswog and Jessica Theissen and Dieter Beule and Hedwig Deubzer and Sascha Sauer and Joern Toedling and Matthias Fischer and Falk Hertwig and Roland F Schwarz and Angelika Eggert and David Torrents and Johannes H Schulte and Anton G Henssen},

doi = {10.1038/s41588-019-0547-z},

issn = {1546-1718},

year  = {2020},

date = {2020-01-01},

journal = {Nat Genet},

volume = {52},

number = {1},

pages = {29--34},

abstract = {Extrachromosomal circularization of DNA is an important genomic feature in cancer. However, the structure, composition and genome-wide frequency of extrachromosomal circular DNA have not yet been profiled extensively. Here, we combine genomic and transcriptomic approaches to describe the landscape of extrachromosomal circular DNA in neuroblastoma, a tumor arising in childhood from primitive cells of the sympathetic nervous system. Our analysis identifies and characterizes a wide catalog of somatically acquired and undescribed extrachromosomal circular DNAs. Moreover, we find that extrachromosomal circular DNAs are an unanticipated major source of somatic rearrangements, contributing to oncogenic remodeling through chimeric circularization and reintegration of circular DNA into the linear genome. Cancer-causing lesions can emerge out of circle-derived rearrangements and are associated with adverse clinical outcome. It is highly probable that circle-derived rearrangements represent an ongoing mutagenic process. Thus, extrachromosomal circular DNAs represent a multihit mutagenic process, with important functional and clinical implications for the origins of genomic remodeling in cancer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32296437,

title = {Tumor-Derived Extracellular Vesicles Impair CD171-Specific CD4 CAR T Cell Efficacy},

author = {Solin Ali and Karin Toews and Silke Schwiebert and Anika Klaus and Annika Winkler and Laura Grunewald and Lena Oevermann and Hedwig E Deubzer and Alicia Tüns and Michael C Jensen and Anton G Henssen and Angelika Eggert and Johannes H Schulte and Esther Schwich and Vera Rebmann and Alexander Schramm and Annette Künkele},

doi = {10.3389/fimmu.2020.00531},

issn = {1664-3224},

year  = {2020},

date = {2020-01-01},

journal = {Front Immunol},

volume = {11},

pages = {531},

abstract = {Chimeric antigen receptor (CAR) T cell efficacy against solid tumors is currently limited by several immune escape mechanisms, which may include tumor-derived extracellular vesicles. Advanced neuroblastoma is an aggressive childhood tumor without curative treatment options for most relapsed patients today. We here evaluated the role of tumor-derived extracellular vesicles on the efficacy of CAR T cells targeting the neuroblastoma-specific antigen, CD171. For this purpose, CAR T cell activation, cytokine production, exhaustion, and tumor cell-directed cytotoxicity upon co-culture was evaluated. Tumor-derived extracellular vesicles isolated from SH-SY5Y neuroblastoma cells neither affected CAR T cell activation nor expression of inhibitory markers. Importantly, exposure of CD4 CD171-specific CAR T cells to tumor-derived extracellular vesicles significantly impaired tumor cytotoxicity of CAR T cells. This effect was independent of neurotrophic receptor tyrosine kinases 1 or 2 (NTRK1, NTRK2) expression, which is known to impact immune responses against neuroblastoma. Our results demonstrate for the first time the impact of tumor-derived extracellular vesicles and non-cell-mediated tumor-suppressive effects on CD4 CAR T cell efficacy in a preclinical setting. We conclude that these factors should be considered for any CAR T cell-based therapy to make CAR T cell therapy successful against solid tumors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31500597,

title = {CD171- and GD2-specific CAR-T cells potently target retinoblastoma cells in preclinical in vitro testing},

author = {Lena Andersch and Josefine Radke and Anika Klaus and Silke Schwiebert and Annika Winkler and Elisa Schumann and Laura Grunewald and Felix Zirngibl and Carina Flemmig and Michael C Jensen and Claudia Rossig and Antonia Joussen and Anton Henssen and Angelika Eggert and Johannes H Schulte and Annette Künkele},

doi = {10.1186/s12885-019-6131-1},

issn = {1471-2407},

year  = {2019},

date = {2019-09-01},

journal = {BMC Cancer},

volume = {19},

number = {1},

pages = {895},

abstract = {BACKGROUND: Chimeric antigen receptor (CAR)-based T cell therapy is in early clinical trials to target the neuroectodermal tumor, neuroblastoma. No preclinical or clinical efficacy data are available for retinoblastoma to date. Whereas unilateral intraocular retinoblastoma is cured by enucleation of the eye, infiltration of the optic nerve indicates potential diffuse scattering and tumor spread leading to a major therapeutic challenge. CAR-T cell therapy could improve the currently limited therapeutic strategies for metastasized retinoblastoma by simultaneously killing both primary tumor and metastasizing malignant cells and by reducing chemotherapy-related late effects.nnMETHODS: CD171 and GD2 expression was flow cytometrically analyzed in 11 retinoblastoma cell lines. CD171 expression and T cell infiltration (CD3) was immunohistochemically assessed in retrospectively collected primary retinoblastomas. The efficacy of CAR-T cells targeting the CD171 and GD2 tumor-associated antigens was preclinically tested against three antigen-expressing retinoblastoma cell lines. CAR-T cell activation and exhaustion were assessed by cytokine release assays and flow cytometric detection of cell surface markers, and killing ability was assessed in cytotoxic assays. CAR constructs harboring different extracellular spacer lengths (short/long) and intracellular co-stimulatory domains (CD28/4-1BB) were compared to select the most potent constructs.nnRESULTS: All retinoblastoma cell lines investigated expressed CD171 and GD2. CD171 was expressed in 15/30 primary retinoblastomas. Retinoblastoma cell encounter strongly activated both CD171-specific and GD2-specific CAR-T cells. Targeting either CD171 or GD2 effectively killed all retinoblastoma cell lines examined. Similar activation and killing ability for either target was achieved by all CAR constructs irrespective of the length of the extracellular spacers and the co-stimulatory domain. Cell lines differentially lost tumor antigen expression upon CAR-T cell encounter, with CD171 being completely lost by all tested cell lines and GD2 further down-regulated in cell lines expressing low GD2 levels before CAR-T cell challenge. Alternating the CAR-T cell target in sequential challenges enhanced retinoblastoma cell killing.nnCONCLUSION: Both CD171 and GD2 are effective targets on human retinoblastoma cell lines, and CAR-T cell therapy is highly effective against retinoblastoma in vitro. Targeting of two different antigens by sequential CAR-T cell applications enhanced tumor cell killing and preempted tumor antigen loss in preclinical testing.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31391345,

title = {Prohibitin is a prognostic marker and therapeutic target to block chemotherapy resistance in Wilms' tumor},

author = {Michael V Ortiz and Saima Ahmed and Melissa Burns and Anton G Henssen and Travis J Hollmann and Ian MacArthur and Shehana Gunasekera and Lyvia Gaewsky and Gary Bradwin and Jeremy Ryan and Anthony Letai and Ying He and Arlene Naranjo and Yueh-Yun Chi and Michael LaQuaglia and Todd Heaton and Paolo Cifani and Jeffrey S Dome and Samantha Gadd and Elizabeth Perlman and Elizabeth Mullen and Hanno Steen and Alex Kentsis},

doi = {10.1172/jci.insight.127098},

issn = {2379-3708},

year  = {2019},

date = {2019-08-01},

journal = {JCI Insight},

volume = {4},

number = {15},

abstract = {Wilms' tumor is the most common type of childhood kidney cancer. To improve risk stratification and identify novel therapeutic targets for patients with Wilms' tumor, we used high-resolution mass spectrometry proteomics to identify urine tumor markers associated with Wilms' tumor relapse. We determined the urine proteomes at diagnosis of 49 patients with Wilms' tumor, non-Wilms' tumor renal tumors, and age-matched controls, leading to the quantitation of 6520 urine proteins. Supervised analysis revealed specific urine markers of renal rhabdoid tumors, kidney clear cell sarcomas, renal cell carcinomas as well as those detected in patients with cured and relapsed Wilms' tumor. In particular, urine prohibitin was significantly elevated at diagnosis in patients with relapsed as compared with cured Wilms' tumor. In a validation cohort of 139 patients, a specific urine prohibitin ELISA demonstrated that prohibitin concentrations greater than 998 ng/mL at diagnosis were significantly associated with ultimate Wilms' tumor relapse. Immunohistochemical analysis revealed that prohibitin was highly expressed in primary Wilms' tumor specimens and associated with disease stage. Using functional genetic experiments, we found that prohibitin was required for the growth and survival of Wilms' tumor cells. Overexpression of prohibitin was sufficient to block intrinsic mitochondrial apoptosis and to cause resistance to diverse chemotherapy drugs, at least in part by dysregulating factors that control apoptotic cytochrome c release from mitochondrial cristae. Thus, urine prohibitin may improve therapy stratification, noninvasive monitoring of treatment response, and early disease detection. In addition, therapeutic targeting of chemotherapy resistance induced by prohibitin dysregulation may offer improved therapies for patients with Wilms' and other relapsed or refractory tumors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30998507,

title = {Prohibitin promotes de-differentiation and is a potential therapeutic target in neuroblastoma},

author = {Ian C MacArthur and Yi Bei and Heathcliff Dorado Garcia and Michael V Ortiz and Joern Toedling and Filippos Klironomos and Jana Rolff and Angelika Eggert and Johannes H Schulte and Alex Kentsis and Anton G Henssen},

doi = {10.1172/jci.insight.127130},

issn = {2379-3708},

year  = {2019},

date = {2019-04-01},

journal = {JCI Insight},

volume = {5},

number = {10},

abstract = {Gain of the long arm of chromosome 17 (17q) is a cytogenetic hallmark of high-risk neuroblastoma, yet its contribution to neuroblastoma pathogenesis remains incompletely understood. Combining whole-genome and RNA sequencing of neuroblastomas, we identified the prohibitin (PHB) gene as highly expressed in tumors with 17q gain. High PHB expression correlated with poor prognosis and was associated with loss of gene expression programs promoting neuronal development and differentiation. PHB depletion induced differentiation and apoptosis and slowed cell cycle progression of neuroblastoma cells, at least in part through impaired ERK1/2 activation. Conversely, ectopic expression of PHB was sufficient to increase proliferation of neuroblastoma cells and was associated with suppression of markers associated with neuronal differentiation and favorable neuroblastoma outcome. Thus, PHB is a 17q oncogene in neuroblastoma that promotes tumor cell proliferation, and de-differentiation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30611741,

title = {Synergistic activity of BET inhibitor MK-8628 and PLK inhibitor Volasertib in preclinical models of medulloblastoma},

author = {Youjia Han and Sven Lindner and Yi Bei and Heathcliff Dorado Garcia and Natalie Timme and Kristina Althoff and Andrea Odersky and Alexander Schramm and Andrej Lissat and Annette Künkele and Hedwig E Deubzer and Angelika Eggert and Johannes H Schulte and Anton G Henssen},

doi = {10.1016/j.canlet.2018.12.012},

issn = {1872-7980},

year  = {2019},

date = {2019-03-01},

journal = {Cancer Lett},

volume = {445},

pages = {24--33},

abstract = {Medulloblastoma is the most prevalent central nervous system tumor in children. Targeted treatment approaches for patients with high-risk medulloblastoma are needed as current treatment regimens are not curative in many cases and cause significant therapy-related morbidity. Medulloblastoma harboring MYC amplification have the most aggressive clinical course and worst outcome. Targeting the BET protein BRD4 has significant anti-tumor effects in preclinical models of MYC-amplified medulloblastoma, however, in most cases these are not curative. We here assessed the therapeutic efficacy of the orally bioavailable BRD4 inhibitor, MK-8628, in preclinical models of medulloblastoma. MK-8628 showed therapeutic efficacy against in vitro and in vivo models of MYC-amplified medulloblastoma by inducing apoptotic cell death and cell cycle arrest. Gene expression analysis of cells treated with MK-8628 showed that anti-tumor effects were accompanied by significant repression of MYC transcription as well as disruption of MYC-regulated transcriptional programs. Additionally, we found that targeting of MYC protein stability through pharmacological PLK1 inhibition showed synergistic anti-medulloblastoma effects when combined with MK-8628 treatment. Thus, MK-8628 is effective against preclinical high-risk medulloblastoma models and its effects can be enhanced through simultaneous targeting of PLK1.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31921698,

title = {Current and Future Treatment Strategies for Rhabdomyosarcoma},

author = {Celine Chen and Heathcliff Dorado Garcia and Monika Scheer and Anton G Henssen},

doi = {10.3389/fonc.2019.01458},

issn = {2234-943X},

year  = {2019},

date = {2019-01-01},

journal = {Front Oncol},

volume = {9},

pages = {1458},

abstract = {Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, and can be subcategorized histologically and/or based on PAX-FOXO1 fusion gene status. Over the last four decades, there have been no significant improvements in clinical outcomes for advanced and metastatic RMS patients, underscoring a need for new treatment options for these groups. Despite significant advancements in our understanding of the genomic landscape and underlying biological mechanisms governing RMS that have informed the identification of novel therapeutic targets, development of these therapies in clinical trials has lagged far behind. In this review, we summarize the current frontline multi-modality therapy for RMS according to pediatric protocols, highlight emerging targeted therapies and immunotherapies identified by preclinical studies, and discuss early clinical trial data and the implications they hold for future clinical development.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30451831,

title = {TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets},

author = {Bieke Decaesteker and Geertrui Denecker and Christophe Van Neste and Emmy M Dolman and Wouter Van Loocke and Moritz Gartlgruber and Carolina Nunes and Fanny De Vloed and Pauline Depuydt and Karen Verboom and Dries Rombaut and Siebe Loontiens and Jolien De Wyn and Waleed M Kholosy and Bianca Koopmans and Anke H W Essing and Carl Herrmann and Daniel Dreidax and Kaat Durinck and Dieter Deforce and Filip Van Nieuwerburgh and Anton Henssen and Rogier Versteeg and Valentina Boeva and Gudrun Schleiermacher and Johan van Nes and Pieter Mestdagh and Suzanne Vanhauwaert and Johannes H Schulte and Frank Westermann and Jan J Molenaar and Katleen De Preter and Frank Speleman},

doi = {10.1038/s41467-018-06699-9},

issn = {2041-1723},

year  = {2018},

date = {2018-11-01},

journal = {Nat Commun},

volume = {9},

number = {1},

pages = {4866},

abstract = {Chromosome 17q gains are almost invariably present in high-risk neuroblastoma cases. Here, we perform an integrative epigenomics search for dosage-sensitive transcription factors on 17q marked by H3K27ac defined super-enhancers and identify TBX2 as top candidate gene. We show that TBX2 is a constituent of the recently established core regulatory circuitry in neuroblastoma with features of a cell identity transcription factor, driving proliferation through activation of p21-DREAM repressed FOXM1 target genes. Combined MYCN/TBX2 knockdown enforces cell growth arrest suggesting that TBX2 enhances MYCN sustained activation of FOXM1 targets. Targeting transcriptional addiction by combined CDK7 and BET bromodomain inhibition shows synergistic effects on cell viability with strong repressive effects on CRC gene expression and p53 pathway response as well as several genes implicated in transcriptional regulation. In conclusion, we provide insight into the role of the TBX2 CRC gene in transcriptional dependency of neuroblastoma cells warranting clinical trials using BET and CDK7 inhibitors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30333322,

title = {Emerging functions of DNA transposases and oncogenic mutators in childhood cancer development},

author = {Anton G Henssen and Alex Kentsis},

doi = {10.1172/jci.insight.123172},

issn = {2379-3708},

year  = {2018},

date = {2018-10-01},

journal = {JCI Insight},

volume = {3},

number = {20},

abstract = {Our understanding of the molecular pathogenesis of childhood cancers has advanced substantially, but their fundamental causes remain poorly understood. Recently, multiple mechanisms of DNA damage and repair have been associated with mutations observed in human cancers. Here, we review the physiologic functions and oncogenic activities of transposable genetic elements. In particular, we focus on the recent studies implicating DNA transposases RAG1/2 and PGBD5 as oncogenic mutators that promote genomic rearrangements in childhood leukemias and solid tumors. We outline future studies that will be needed to define the contributions of transposons to mutational processes that become dysregulated in cancer cells. In addition, we discuss translational approaches, including synthetic lethal strategies, for identifying and developing improved clinical therapies to target oncogenic transposons and transposases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29093183,

title = {Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors},

author = {Anton G Henssen and Casie Reed and Eileen Jiang and Heathcliff Dorado Garcia and Jennifer von Stebut and Ian C MacArthur and Patrick Hundsdoerfer and Jun Hyun Kim and Elisa de Stanchina and Yasumichi Kuwahara and Hajime Hosoi and Neil J Ganem and Filemon Dela Cruz and Andrew L Kung and Johannes H Schulte and John H Petrini and Alex Kentsis},

doi = {10.1126/scitranslmed.aam9078},

issn = {1946-6242},

year  = {2017},

date = {2017-11-01},

journal = {Sci Transl Med},

volume = {9},

number = {414},

abstract = {Despite intense efforts, the cure rates of childhood and adult solid tumors are not satisfactory. Resistance to intensive chemotherapy is common, and targets for molecular therapies are largely undefined. We have found that the majority of childhood solid tumors, including rhabdoid tumors, neuroblastoma, medulloblastoma, and Ewing sarcoma, express an active DNA transposase, , that can promote site-specific genomic rearrangements in human cells. Using functional genetic approaches, we discovered that mouse and human cells deficient in nonhomologous end joining (NHEJ) DNA repair cannot tolerate the expression of PGBD5. In a chemical screen of DNA damage signaling inhibitors, we identified AZD6738 as a specific sensitizer of PGBD5-dependent DNA damage and apoptosis. We found that expression of PGBD5, but not its nuclease activity-deficient mutant, was sufficient to induce sensitivity to AZD6738. Depletion of endogenous PGBD5 conferred resistance to AZD6738 in human tumor cells. PGBD5-expressing tumor cells accumulated unrepaired DNA damage in response to AZD6738 treatment and underwent apoptosis in both dividing and G-phase cells in the absence of immediate DNA replication stress. Accordingly, AZD6738 exhibited nanomolar potency against most neuroblastoma, medulloblastoma, Ewing sarcoma, and rhabdoid tumor cells tested while sparing nontransformed human and mouse embryonic fibroblasts in vitro. Finally, treatment with AZD6738 induced apoptosis and regression of human neuroblastoma and medulloblastoma tumors engrafted in immunodeficient mice in vivo. This effect was potentiated by combined treatment with cisplatin, including substantial antitumor activity against patient-derived primary neuroblastoma xenografts. These findings delineate a therapeutically actionable synthetic dependency induced in PGBD5-expressing solid tumors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28951624,

title = {Erratum: PGBD5 promotes site-specific oncogenic mutations in human tumors},

author = {Anton G Henssen and Richard Koche and Jiali Zhuang and Eileen Jiang and Casie Reed and Amy Eisenberg and Eric Still and Ian C MacArthur and Elias Rodríguez-Fos and Santiago Gonzalez and Montserrat Puiggròs and Andrew N Blackford and Christopher E Mason and Elisa de Stanchina and Mithat Gönen and Anne-Katrin Emde and Minita Shah and Kanika Arora and Catherine Reeves and Nicholas D Socci and Elizabeth Perlman and Cristina R Antonescu and Charles W M Roberts and Hanno Steen and Elizabeth Mullen and Stephen P Jackson and David Torrents and Zhiping Weng and Scott A Armstrong and Alex Kentsis},

doi = {10.1038/ng1017-1558b},

issn = {1546-1718},

year  = {2017},

date = {2017-09-01},

journal = {Nat Genet},

volume = {49},

number = {10},

pages = {1558},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28504702,

title = {PGBD5 promotes site-specific oncogenic mutations in human tumors},

author = {Anton G Henssen and Richard Koche and Jiali Zhuang and Eileen Jiang and Casie Reed and Amy Eisenberg and Eric Still and Ian C MacArthur and Elias Rodríguez-Fos and Santiago Gonzalez and Montserrat Puiggròs and Andrew N Blackford and Christopher E Mason and Elisa de Stanchina and Mithat Gönen and Anne-Katrin Emde and Minita Shah and Kanika Arora and Catherine Reeves and Nicholas D Socci and Elizabeth Perlman and Cristina R Antonescu and Charles W M Roberts and Hanno Steen and Elizabeth Mullen and Stephen P Jackson and David Torrents and Zhiping Weng and Scott A Armstrong and Alex Kentsis},

doi = {10.1038/ng.3866},

issn = {1546-1718},

year  = {2017},

date = {2017-07-01},

journal = {Nat Genet},

volume = {49},

number = {7},

pages = {1005--1014},

abstract = {Genomic rearrangements are a hallmark of human cancers. Here, we identify the piggyBac transposable element derived 5 (PGBD5) gene as encoding an active DNA transposase expressed in the majority of childhood solid tumors, including lethal rhabdoid tumors. Using assembly-based whole-genome DNA sequencing, we found previously undefined genomic rearrangements in human rhabdoid tumors. These rearrangements involved PGBD5-specific signal (PSS) sequences at their breakpoints and recurrently inactivated tumor-suppressor genes. PGBD5 was physically associated with genomic PSS sequences that were also sufficient to mediate PGBD5-induced DNA rearrangements in rhabdoid tumor cells. Ectopic expression of PGBD5 in primary immortalized human cells was sufficient to promote cell transformation in vivo. This activity required specific catalytic residues in the PGBD5 transposase domain as well as end-joining DNA repair and induced structural rearrangements with PSS breakpoints. These results define PGBD5 as an oncogenic mutator and provide a plausible mechanism for site-specific DNA rearrangements in childhood and adult solid tumors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27888795,

title = {Targeting tachykinin receptors in neuroblastoma},

author = {Anton G Henssen and Andrea Odersky and Annabell Szymansky and Marleen Seiler and Kristina Althoff and Anneleen Beckers and Frank Speleman and Simon Schäfers and Katleen De Preter and Kathy Astrahanseff and Joachim Struck and Alexander Schramm and Angelika Eggert and Andreas Bergmann and Johannes H Schulte},

doi = {10.18632/oncotarget.13440},

issn = {1949-2553},

year  = {2017},

date = {2017-01-01},

journal = {Oncotarget},

volume = {8},

number = {1},

pages = {430--443},

abstract = {Neuroblastoma is the most common extracranial tumor in children. Despite aggressive multimodal treatment, high-risk neuroblastoma remains a clinical challenge with survival rates below 50%. Adding targeted drugs to first-line therapy regimens is a promising approach to improve survival in these patients. TACR1 activation by substance P has been reported to be mitogenic in cancer cell lines. Tachykinin receptor (TACR1) antagonists are approved for clinical use as an antiemetic remedy since 2003. Tachykinin receptor inhibition has recently been shown to effectively reduce growth of several tumor types. Here, we report that neuroblastoma cell lines express TACR1, and that targeting TACR1 activity significantly reduced cell viability and induced apoptosis in neuroblastoma cell lines. Gene expression profiling revealed that TACR1 inhibition repressed E2F2 and induced TP53 signaling. Treating mice harboring established neuroblastoma xenograft tumors with Aprepitant also significantly reduced tumor burden. Thus, we provide evidence that the targeted inhibition of tachykinin receptor signaling shows therapeutic efficacy in preclinical models for high-risk neuroblastoma.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27491780,

title = {Forward genetic screen of human transposase genomic rearrangements},

author = {Anton G Henssen and Eileen Jiang and Jiali Zhuang and Luca Pinello and Nicholas D Socci and Richard Koche and Mithat Gonen and Camila M Villasante and Scott A Armstrong and Daniel E Bauer and Zhiping Weng and Alex Kentsis},

doi = {10.1186/s12864-016-2877-x},

issn = {1471-2164},

year  = {2016},

date = {2016-08-01},

journal = {BMC Genomics},

volume = {17},

pages = {548},

abstract = {BACKGROUND: Numerous human genes encode potentially active DNA transposases or recombinases, but our understanding of their functions remains limited due to shortage of methods to profile their activities on endogenous genomic substrates.nnRESULTS: To enable functional analysis of human transposase-derived genes, we combined forward chemical genetic hypoxanthine-guanine phosphoribosyltransferase 1 (HPRT1) screening with massively parallel paired-end DNA sequencing and structural variant genome assembly and analysis. Here, we report the HPRT1 mutational spectrum induced by the human transposase PGBD5, including PGBD5-specific signal sequences (PSS) that serve as potential genomic rearrangement substrates.nnCONCLUSIONS: The discovered PSS motifs and high-throughput forward chemical genomic screening approach should prove useful for the elucidation of endogenous genome remodeling activities of PGBD5 and other domesticated human DNA transposases and recombinases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26631615,

title = {Targeting MYCN-Driven Transcription By BET-Bromodomain Inhibition},

author = {Anton Henssen and Kristina Althoff and Andrea Odersky and Anneleen Beckers and Richard Koche and Frank Speleman and Simon Schäfers and Emma Bell and Maike Nortmeyer and Frank Westermann and Katleen De Preter and Alexandra Florin and Lukas Heukamp and Annika Spruessel and Kathy Astrahanseff and Sven Lindner and Natalie Sadowski and Alexander Schramm and Lucile Astorgues-Xerri and Maria E Riveiro and Angelika Eggert and Esteban Cvitkovic and Johannes H Schulte},

doi = {10.1158/1078-0432.CCR-15-1449},

issn = {1557-3265},

year  = {2016},

date = {2016-05-01},

journal = {Clin Cancer Res},

volume = {22},

number = {10},

pages = {2470--2481},

abstract = {PURPOSE: Targeting BET proteins was previously shown to have specific antitumoral efficacy against MYCN-amplified neuroblastoma. We here assess the therapeutic efficacy of the BET inhibitor, OTX015, in preclinical neuroblastoma models and extend the knowledge on the role of BRD4 in MYCN-driven neuroblastoma.nnEXPERIMENTAL DESIGN: The efficacy of OTX015 was assessed in in vitro and in vivo models of human and murine MYCN-driven neuroblastoma. To study the effects of BET inhibition in the context of high MYCN levels, MYCN was ectopically expressed in human and murine cells. The effect of OTX015 on BRD4-regulated transcriptional pause release was analyzed using BRD4 and H3K27Ac chromatin immunoprecipitation coupled with DNA sequencing (ChIP-Seq) and gene expression analysis in neuroblastoma cells treated with OTX015 compared with vehicle control.nnRESULTS: OTX015 showed therapeutic efficacy against preclinical MYCN-driven neuroblastoma models. Similar to previously described BET inhibitors, concurrent MYCN repression was observed in OTX015-treated samples. Ectopic MYCN expression, however, did not abrogate effects of OTX015, indicating that MYCN repression is not the only target of BET proteins in neuroblastoma. When MYCN was ectopically expressed, BET inhibition still disrupted MYCN target gene transcription without affecting MYCN expression. We found that BRD4 binds to super-enhancers and MYCN target genes, and that OTX015 specifically disrupts BRD4 binding and transcription of these genes.nnCONCLUSIONS: We show that OTX015 is effective against mouse and human MYCN-driven tumor models and that BRD4 not only targets MYCN, but specifically occupies MYCN target gene enhancers as well as other genes associated with super-enhancers. Clin Cancer Res; 22(10); 2470-81. ©2015 AACR.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26735709,

title = {Cytoarchitecture and probability maps of the human medial orbitofrontal cortex},

author = {Anton Henssen and Karl Zilles and Nicola Palomero-Gallagher and Axel Schleicher and Hartmut Mohlberg and Fatma Gerboga and Simon B Eickhoff and Sebastian Bludau and Katrin Amunts},

doi = {10.1016/j.cortex.2015.11.006},

issn = {1973-8102},

year  = {2016},

date = {2016-02-01},

journal = {Cortex},

volume = {75},

pages = {87--112},

abstract = {Previous architectonical studies of human orbitofrontal cortex (OFC) provided divergent maps regarding number, location, and extent of areas. To solve this controversy, an observer-independent cytoarchitectonical mapping of medial OFC (mOFC) was performed. Borders of cortical areas were detected in histological sections of ten human post-mortem brains using a quantitative, statistically testable method, and their stereotaxic localization and intersubject variability were determined. Three areas were identified: granular Fo1 mainly on the rostral Gyrus rectus and medial of the olfactory sulcus; granular to dysgranular Fo2, mainly on the posterior part of the ventromedial Gyrus rectus and the medial and lateral banks of the olfactory sulcus; granular Fo3 between the olfactory and medial or intermediate orbital sulci. Fo3 was bordered medially by Fo1 and Fo2 and laterally by the lateral OFC (lOFC). A cluster analysis of the cytoarchitectonical features of Fo1-Fo3, subgenual cingulate areas, BA12, lateral and medial areas of the frontopolar cortex, lOFC and areas of Broca's region demonstrated the cytoarchitectonical similarity between the mOFC areas in contrast to all other frontal areas. Probabilistic maps of mOFC areas show a considerable intersubject variability in extent and position in stereotaxic space, and provide spatial templates for anatomical localization of in vivo neuroimaging data via the JuBrain atlas and the Anatomy Toolbox.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26406119,

title = {Genomic DNA transposition induced by human PGBD5},

author = {Anton G Henssen and Elizabeth Henaff and Eileen Jiang and Amy R Eisenberg and Julianne R Carson and Camila M Villasante and Mondira Ray and Eric Still and Melissa Burns and Jorge Gandara and Cedric Feschotte and Christopher E Mason and Alex Kentsis},

doi = {10.7554/eLife.10565},

issn = {2050-084X},

year  = {2015},

date = {2015-09-01},

journal = {Elife},

volume = {4},

abstract = {Transposons are mobile genetic elements that are found in nearly all organisms, including humans. Mobilization of DNA transposons by transposase enzymes can cause genomic rearrangements, but our knowledge of human genes derived from transposases is limited. In this study, we find that the protein encoded by human PGBD5, the most evolutionarily conserved transposable element-derived gene in vertebrates, can induce stereotypical cut-and-paste DNA transposition in human cells. Genomic integration activity of PGBD5 requires distinct aspartic acid residues in its transposase domain, and specific DNA sequences containing inverted terminal repeats with similarity to piggyBac transposons. DNA transposition catalyzed by PGBD5 in human cells occurs genome-wide, with precise transposon excision and preference for insertion at TTAA sites. The apparent conservation of DNA transposition activity by PGBD5 suggests that genomic remodeling contributes to its biological function.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26121086,

title = {Mutational dynamics between primary and relapse neuroblastomas},

author = {Alexander Schramm and Johannes Köster and Yassen Assenov and Kristina Althoff and Martin Peifer and Ellen Mahlow and Andrea Odersky and Daniela Beisser and Corinna Ernst and Anton G Henssen and Harald Stephan and Christopher Schröder and Lukas Heukamp and Anne Engesser and Yvonne Kahlert and Jessica Theissen and Barbara Hero and Frederik Roels and Janine Altmüller and Peter Nürnberg and Kathy Astrahantseff and Christian Gloeckner and Katleen De Preter and Christoph Plass and Sangkyun Lee and Holger N Lode and Kai-Oliver Henrich and Moritz Gartlgruber and Frank Speleman and Peter Schmezer and Frank Westermann and Sven Rahmann and Matthias Fischer and Angelika Eggert and Johannes H Schulte},

doi = {10.1038/ng.3349},

issn = {1546-1718},

year  = {2015},

date = {2015-08-01},

journal = {Nat Genet},

volume = {47},

number = {8},

pages = {872--877},

abstract = {Neuroblastoma is a malignancy of the developing sympathetic nervous system that is often lethal when relapse occurs. We here used whole-exome sequencing, mRNA expression profiling, array CGH and DNA methylation analysis to characterize 16 paired samples at diagnosis and relapse from individuals with neuroblastoma. The mutational burden significantly increased in relapsing tumors, accompanied by altered mutational signatures and reduced subclonal heterogeneity. Global allele frequencies at relapse indicated clonal mutation selection during disease progression. Promoter methylation patterns were consistent over disease course and were patient specific. Recurrent alterations at relapse included mutations in the putative CHD5 neuroblastoma tumor suppressor, chromosome 9p losses, DOCK8 mutations, inactivating mutations in PTPN14 and a relapse-specific activity pattern for the PTPN14 target YAP. Recurrent new mutations in HRAS, KRAS and genes mediating cell-cell interaction in 13 of 16 relapse tumors indicate disturbances in signaling pathways mediating mesenchymal transition. Our data shed light on genetic alteration frequency, identity and evolution in neuroblastoma.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25351246,

title = {ALK pERKs up MYCN in neuroblastoma},

author = {Sven Lindner and Anton Henssen and Kathy Astrahantseff and Johannes H Schulte},

doi = {10.1126/scisignal.2005940},

issn = {1937-9145},

year  = {2014},

date = {2014-10-01},

journal = {Sci Signal},

volume = {7},

number = {349},

pages = {pe27},

abstract = {The gene expressing the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) is mutated and aberrantly expressed in several cancers. The clinical efficacy of the ALK inhibitor, crizotinib, lags behind expectations for treating MYCN-amplified, ALK-mutant neuroblastoma, a deadly childhood cancer. In this issue of Science Signaling, Umapathy et al. identify the kinase extracellular signal-regulated kinase 5 (ERK5) as a central mediator that enables ALK to boost MYCN expression, and they show that inhibiting ERK5 in concert with ALK reduced neuroblastoma cell viability in vitro and in xenograft tumor models. This report has important clinical implications for the treatment of patients with neuroblastoma or other tumors that overexpress MYC(N) and harbor ALK mutations, such as non-small-cell lung cancer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24231268,

title = {BET bromodomain protein inhibition is a therapeutic option for medulloblastoma},

author = {Anton Henssen and Theresa Thor and Andrea Odersky and Lukas Heukamp and Nicolai El-Hindy and Anneleen Beckers and Frank Speleman and Kristina Althoff and Simon Schäfers and Alexander Schramm and Ulrich Sure and Gudrun Fleischhack and Angelika Eggert and Johannes H Schulte},

doi = {10.18632/oncotarget.1534},

issn = {1949-2553},

year  = {2013},

date = {2013-11-01},

journal = {Oncotarget},

volume = {4},

number = {11},

pages = {2080--2095},

abstract = {Medulloblastoma is the most common malignant brain tumor of childhood, and represents a significant clinical challenge in pediatric oncology, since overall survival currently remains under 70%. Patients with tumors overexpressing MYC or harboring a MYC oncogene amplification have an extremely poor prognosis. Pharmacologically inhibiting MYC expression may, thus, have clinical utility given its pathogenetic role in medulloblastoma. Recent studies using the selective small molecule BET inhibitor, JQ1, have identified BET bromodomain proteins, especially BRD4, as epigenetic regulatory factors for MYC and its targets. Targeting MYC expression by BET inhibition resulted in antitumoral effects in various cancers. Our aim here was to evaluate the efficacy of JQ1 against preclinical models for high-risk MYC-driven medulloblastoma. Treatment of medulloblastoma cell lines with JQ1 significantly reduced cell proliferation and preferentially induced apoptosis in cells expressing high levels of MYC. JQ1 treatment of medulloblastoma cell lines downregulated MYC expression and resulted in a transcriptional deregulation of MYC targets, and also significantly altered expression of genes involved in cell cycle progression and p53 signalling. JQ1 treatment prolonged the survival of mice harboring medulloblastoma xenografts and reduced the tumor burden in these mice. Our preclinical data provide evidence to pursue testing BET inhibitors, such as JQ1, as molecular targeted therapeutic options for patients with high-risk medulloblastomas overexpressing MYC or harboring MYC amplifications.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}