Review
Biochemistry & Molecular Biology
Soraya Epp, Shin Mei Chuah, Melinda Halasz
Summary: This review examines the intricate interplay between MYCN and known epigenetic mechanisms in neuroblastoma, and provides insights into emerging therapeutic strategies targeting these mechanisms to improve patient outcomes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cell Biology
Xiaoling Zhang, Xianling Cong, Xiangting Jin, Yu'e Liu, Tong Zhang, Xinyuan Fan, Xiyao Shi, Xiaoying Zhang, Xue Wang, Yong-Guang Yang, Xiangpeng Dai
Summary: The transcription factor MYCN is frequently amplified and overexpressed in various cancers, and is considered undruggable. In this study, BRCA1-associated protein-1 (BAP1) is identified as an upstream regulator that stabilizes MYCN through direct binding. Depletion of BAP1 inhibits neuroblastoma tumor cell growth and migration, and confers cellular resistance to BET protein inhibitor JQ1 and Aurora A kinase inhibitor Alisertib. Our findings suggest that BAP1 could be a potential therapeutic target for MYCN-amplified neuroblastoma.
CELL DEATH & DISEASE
(2023)
Article
Multidisciplinary Sciences
Hai-Feng Zhang, Alberto Delaidelli, Sumreen Javed, Busra Turgu, Taylor Morrison, Christopher S. Hughes, Xiaqiu Yang, Manideep Pachva, Michael M. Lizardo, Gurdeep Singh, Jennifer Hoffmann, Yue Zhou Huang, Khushbu Patel, Rawan Shraim, Sonia H. Y. Kung, Gregg B. Morin, Samuel Aparicio, Daniel Martinez, John M. Maris, Kristopher R. Bosse, Karla C. Williams, Poul H. Sorensen
Summary: This study reveals that GREB1 gene, located near MYCN locus, is frequently coexpressed with MYCN and promotes cell survival in high-risk neuroblastoma (NB). The research also identifies MYO1B gene as a crucial regulator of invasion and metastasis in MYCN amplified NB. Furthermore, MYO1B is found to regulate secretome reprogramming and the cytokine MIF mediates its pro-invasive and pro-metastatic activity.
Article
Oncology
Danny Misiak, Sven Hagemann, Jessica L. Bell, Bianca Busch, Marcell Lederer, Nadine Bley, Johannes H. Schulte, Stefan Huttelmaier
Summary: MYCN gene amplification and upregulated expression are critical in high-risk neuroblastoma progression. MYCN is tightly regulated in neuroblastoma, including post-transcriptional control and modulation of microRNA expression. Dysregulation of MYCN expression and miRNAs is associated with neuroblastoma pathogenesis, with potential implications for therapeutic targeting.
FRONTIERS IN ONCOLOGY
(2021)
Article
Oncology
Silvia Lampis, Salvatore Raieli, Luca Montemurro, Damiano Bartolucci, Camilla Amadesi, Sonia Bortolotti, Silvia Angelucci, Anna Lisa Scardovi, Giammario Nieddu, Lucia Cerisoli, Francesca Paganelli, Sabrina Valente, Matthias Fischer, Alberto Maria Martelli, Gianandrea Pasquinelli, Andrea Pession, Patrizia Hrelia, Roberto Tonelli
Summary: This study found that the combination of MYCN-specific antigene oligonucleotide BGA002 and retinoic acid (RA) can restore sensitivity to RA in MYCN-amplified neuroblastoma (MNA-NB) patients and improve their survival rate. Furthermore, by targeting MYCN, a cancer-specific inhibition of the mTOR pathway occurs only in MNA-NB, avoiding the side effects of targeting mTOR in normal cells.
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
(2022)
Article
Oncology
Kezhe Tan, Jialin Mo, Meng Li, Yu Dong, Yujie Han, Xi Sun, Yingxuan Ma, Kai Zhu, Wei Wu, Li Lu, Jiangbin Liu, Kewen Zhao, Lei Zhang, Yujie Tang, Zhibao Lv
Summary: This study reveals the important role of SMAD9 in neuroblastoma and its positive transcriptional feedback loop with MYCN, representing a unique tumor dependency for MYCN-amplified neuroblastoma.
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
(2022)
Article
Oncology
Felix Schmitt-Hoffner, Sjoerd van Rijn, Umut H. Toprak, Monika Mauermann, Felix Rosemann, Anke Heit-Mondrzyk, Jens-Martin Hubner, Aylin Camgoz, Sabine Hartlieb, Stefan M. Pfister, Kai-Oliver Henrich, Frank Westermann, Marcel Kool
Summary: Activation of FOXR2 identifies a subset of neuroblastoma tumors with unfavorable outcomes, potentially related to MYCN; The study confirms the importance of FOXR2 in neuroblastoma through data analysis and cell experiments, indicating its involvement in cell cycle, growth, and death; FOXR2 stabilizes MYCN protein, impacting patient clinical outcomes.
JOURNAL OF CLINICAL ONCOLOGY
(2021)
Article
Oncology
Adam D. Durbin, Tingjian Wang, Virangika K. Wimalasena, Mark W. Zimmerman, Deyao Li, Neekesh Dharia, Luca Mariani, Noha A. M. Shendy, Stephanie Nance, Anand G. Patel, Ying Shao, Maya Mundada, Lily Maxham, Paul M. C. Park, Logan H. Sigua, Ken Morita, Amy Saur Conway, Amanda L. Robichaud, Antonio R. Perez-Atayde, Melissa J. Bikowitz, Taylor R. Quinn, Olaf Wiest, John Easton, Ernst Schonbrunn, Martha L. Bulyk, Brian J. Abraham, Kimberly Stegmaier, A. Thomas Look, Jun Qi
Summary: Gene expression is regulated by histone modifications, and EP300 plays a significant role in high-risk neuroblastoma. The compound JQAD1, which targets EP300, effectively induces cell apoptosis in neuroblastoma cells with limited toxicity to normal cells.
Article
Multidisciplinary Sciences
Donghai Wang, Zhinang Yin, Honghong Wang, Liyuan Wang, Tianyu Li, Ruijing Xiao, Ting Xie, Ruyi Han, Rui Dong, Hudan Liu, Kaiwei Liang, Guoliang Qing
Summary: MYCN amplification in neuroblastoma leads to aberrant expression of MYCN oncoprotein, which activates active genes and enhances transcriptional elongation. Super elongation complex (SEC) is identified as a vulnerability in MYCN-amplified neuroblastomas and is recruited by MYCN to enhance processive transcription elongation. Inhibition of SEC leads to global reduction in transcription elongation and selective apoptosis of MYCN-amplified neuroblastoma cells, and synergistically enhances the therapeutic efficacy of BCL-2 antagonist ABT-199 in MYCN-amplified neuroblastomas.
Article
Oncology
Birte Arlt, Christin Zasada, Katharina Baum, Jasmin Wuenschel, Guido Mastrobuoni, Marco Lodrini, Kathy Astrahantseff, Annika Winkler, Johannes H. Schulte, Sabine Finkler, Martin Forbes, Patrick Hundsdoerfer, Dennis Guergen, Jens Hoffmann, Jana Wolf, Angelika Eggert, Stefan Kempa, Hedwig E. Deubzer
Summary: This study identified a correlation between MYCN amplification and PHGDH protein as well as de novo serine synthesis. MYCN-amplified cells showed independence from exogenous serine and glycine, and PHGDH knockout or inhibition slowed proliferation but did not kill the cells, leading to chemotherapy resistance in neuroblastoma treatment. The limited attractiveness of PHGDH inhibition with small molecules in neuroblastoma patients was also discussed.
INTERNATIONAL JOURNAL OF CANCER
(2021)
Article
Medicine, Research & Experimental
Kausik Bishayee, Uddin Md. Nazim, Vijay Kumar, Jieun Kang, Jaebong Kim, Sung-Oh Huh, Ali Sadra
Summary: In MYCN-amplified neuroblastoma, treatment with the HDAC inhibitor vorinostat leads to a reprogramming of the glycolytic pathway, increasing fatty acid oxidation and oxidative phosphorylation. This reprogramming is correlated with reduced levels of MYCN and increased levels of PPARD transcription factors. Additionally, the combination of HDAC and mTORC1 inhibitors increases reactive oxygen species levels. The glycolytic enzymes HK2 and GPI are most affected by this combination. Overall, this combination treatment shows promising results without causing significant toxicity in mice.
BIOMEDICINE & PHARMACOTHERAPY
(2022)
Article
Oncology
Anders Valind, Bronte Manouk Verhoeven, Jens Enoksson, Jenny Karlsson, Gustav Christensson, Adriana Manas, Kristina Aaltonen, Caroline Jansson, Daniel Bexell, Ninib Baryawno, David Gisselsson, Catharina Hagerling
Summary: Despite aggressive treatment, the 5-year event-free survival rate for children with high-risk neuroblastoma is <50%. Novel therapeutic alternatives that target the immune microenvironment can effectively inhibit the relapse of MNA(+) neuroblastoma.
Article
Multidisciplinary Sciences
Krista M. Dalton, Timothy L. Lochmann, Konstantinos Floros, Marissa L. Calbert, Richard Kurupi, Giovanna T. Stein, Joseph McClanaghan, Ellen Murchie, Regina K. Egan, Patricia Greninger, Mikhail Dozmorov, Sivapriya Ramamoorthy, Madhavi Puchalapalli, Bin Hu, Lisa Shock, Jennifer Koblinski, John Glod, Sosipatros A. Boikos, Cyril H. Benes, Anthony C. Faber
Summary: MYCN-amplified neuroblastoma is sensitive to the combination of the lactate transporter MCT1 inhibitor AZD3965 and the mitochondrial complex I inhibitor phenformin. Low expression of MCT4, combined with high expression of MCT2 and MCT1 chaperone CD147 in MYCN-amplified neuroblastoma, confers sensitivity to this combination therapy, leading to disruption of glycolysis and oxidative phosphorylation, ATP production, endoplasmic reticulum stress, and ultimately, cell death.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Oncology
Tao Liu, Lubing Gu, Zhongzhi Wu, Najah Albadari, Wei Li, Muxiang Zhou
Summary: Amplification of MYCN gene leads to overexpression of MYCN mRNA and protein, which plays a role in promoting neuroblastoma. A small molecule compound MX25-1 can bind to the 3'UTR of MYCN mRNA and induce its degradation, resulting in cell growth inhibition and cell death specifically in MYCN-amplified neuroblastoma cells. The activation of tumor suppressor miRNA let-7 is associated with the anticancer activity of MX25-1.
FRONTIERS IN ONCOLOGY
(2022)
Article
Cell Biology
Yajie Yu, Jane Ding, Shunqin Zhu, Ahmet Alptekin, Zheng Dong, Chunhong Yan, Yunhong Zha, Han-Fei Ding
Summary: Metabolic reprogramming driven by oncogenes like MYC is closely related to growth promotion, but also leads to potential therapeutic metabolic dependencies; MYCN-amplified neuroblastoma promotes pyrimidine nucleotide production by upregulating DHODH and other enzymes, and inhibition of DHODH can effectively suppress proliferation and tumorigenicity of these cancer cells.
CELL DEATH & DISEASE
(2021)
Letter
Hematology
Michael Launspach, Dennis Temel, Emily Ohlendorf, Felix Zirngibl, Bianca Materne, Lena Oevermann, Hedwig E. Deubzer, Anton G. Henssen, Annette Kunkele, Patrick Hundsdorfer, Horst von Bernuth, Axel Pruss, Angelika Eggert, Arend von Stackelberg, Peter Lang, Johannes H. Schulte
Article
Oncology
Florian Selt, Romain Sigaud, Gintvile Valinciute, Philipp Sievers, Julia Zaman, Clara Alco, Simone Schmid, Heike Peterziel, Jessica W. Tsai, Romain Guiho, Juan Pedro Martinez-Barbera, Stefan Pusch, Jing Deng, Yifan Zhai, Cornelis M. van Tilburg, Martin U. Schuhman, Ahmed E. L. Damaty, Pratiti Bandopadhayay, Christel Herold-Mende, Andreas von Deimling, Stefan M. Pfister, Joan Montero, David Capper, Ina Oehme, Felix Sahm, David T. W. Jones, Olaf Witt, Till Milde
Summary: Our study demonstrates that BCL-XL is critical for the survival of senescent PA tumor cells and provides evidence for the use of clinically available BCL-XL-dependent senolytic agents.
Article
Clinical Neurology
Maximilian Deng, Felix Hinz, Semi Harrabi, Dominik Sturm, Martin Sill, Andrey Korshunov, Tanja Eichkorn, Juliane Hoerner-Rieber, Klaus Herfarth, Christine Jungk, Andreas Unterberg, Stefan Pfister, Wolfgang Wick, Andreas von Deimling, David Jones, Juergen Debus, Felix Sahm, Laila Koenig
Summary: Molecular brain tumor classification using DNA methylation profiling has revealed that the methylation-class of pleomorphic xanthoastrocytoma (mcPXA) comprised a substantial portion of divergent initial diagnoses. This study aimed to characterize the survival outcome in patients with mcPXAs and determine the benefit of postoperative radiotherapy. The results demonstrated that adult patients with mcPXAs display a worse progression-free survival compared to the reported WHO grade 2 PXAs.
NEURO-ONCOLOGY PRACTICE
(2023)
Article
Oncology
Venu Thatikonda, S. M. Ashiqul Islam, Robert J. Autry, Barbara C. Jones, Susanne N. Groebner, Gregor Warsow, Barbara Hutter, Daniel Huebschmann, Stefan Froehling, Marcel Kool, Mirjam Blattner-Johnson, David T. W. Jones, Ludmil B. Alexandrov, Stefan M. Pfister, Natalie Jaeger
Summary: Jager and colleagues analyzed the mutational patterns in pediatric cancers and found marked differences compared to adult cancers, providing insights into molecular mechanisms. They identified a small number of mutational signatures specific to pediatric cancers and discovered a previously unreported indel signature in pediatric leukemias. This study provides a systematic overview of mutational signatures in pediatric cancers, which is highly relevant for understanding tumor biology and developing biomarkers for treatment response.
Article
Pediatrics
Marius Ludwig, Alireza Basti, Muege Yalcin, Johannes H. Schulte, Angela Relogio
Summary: This study aims to characterize the circadian clock in pediatric patients with acute leukemia, for the first time. By collecting saliva, blood, and bone marrow samples, the researchers will analyze the expression of core-clock genes. The findings of this study may contribute to adjusting chemotherapy timing and reducing systemic toxicities.
Article
Oncology
Carolina Rosswog, Jana Fassunke, Angela Ernst, Birgid Schoemig-Markiefka, Sabine Merkelbach-Bruse, Christoph Bartenhagen, Maria Cartolano, Sandra Ackermann, Jessica Theissen, Mirjam Blattner-Johnson, Barbara Jones, Kathrin Schramm, Janine Altmueller, Peter Nuernberg, Monika Ortmann, Frank Berthold, Martin Peifer, Reinhard Buettner, Frank Westermann, Johannes H. Schulte, Thorsten Simon, Barbara Hero, Matthias Fischer
Summary: Genomic alterations of the ALK gene occur recurrently in neuroblastoma, with ALK mutations occurring in 10.5% of cases at diagnosis and increasing by 70% at relapse. However, the frequency of ALK amplifications does not change over the course of the disease. Regular monitoring of the genomic ALK status and evaluation of ALK-targeted treatment in intermediate-risk patients is recommended.
BRITISH JOURNAL OF CANCER
(2023)
Letter
Oncology
Christian P. Kratz, Dmitrii Smirnov, Robert Autry, Natalie Jaeger, Sebastian M. Waszak, Anika Grosshennig, Riccardo Berutti, Mareike Wendorff, Pierre Hainaut, Stefan M. Pfister, Holger Prokisch, Tim Ripperger, David Malkin
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
(2023)
Article
Oncology
Krzysztof Mrozek, Jessica Kohlschmidt, James S. Blachly, Deedra Nicolet, Andrew J. Carroll, Kellie J. Archer, Alice S. Mims, Karilyn T. Larkin, Shelley Orwick, Christopher C. Oakes, Jonathan E. Kolitz, Bayard L. Powell, William G. Blum, Guido Marcucci, Maria R. Baer, Geoffrey L. Uy, Wendy Stock, John C. Byrd, Ann-Kathrin Eisfeld
Summary: Recently, the European LeukemiaNet revised the genetic-risk classification of acute myeloid leukemia (AML), leading to changes in the percentage of patients in different risk groups. The new classification accurately reflected treatment outcomes in most patients, but there were discrepancies in certain age and ethnic groups. The prediction abilities of the new and old classifications were similar, and the significance of some newly added markers was confirmed and challenged.
Article
Biochemistry & Molecular Biology
Dominik Sturm, David Capper, Felipe Andreiuolo, Marco Gessi, Christian Koelsche, Annekathrin Reinhardt, Philipp Sievers, Annika K. Wefers, Azadeh Ebrahimi, Abigail K. Suwala, Gerrit H. Gielen, Martin Sill, Daniel Schrimpf, Damian Stichel, Volker Hovestadt, Bjarne Daenekas, Agata Rode, Stefan Hamelmann, Christopher Previti, Natalie Jaeger, Ivo Buchhalter, Mirjam Blattner-Johnson, Barbara C. Jones, Monika Warmuth-Metz, Brigitte Bison, Kerstin Grund, Christian Sutter, Steffen Hirsch, Nicola Dikow, Martin Hasselblatt, Ulrich Schueller, Nicolas U. Gerber, Christine L. White, Molly K. Buntine, Kathryn Kinross, Elizabeth M. Algar, Jordan R. Hansford, Nicholas G. Gottardo, Pablo Hernaiz Driever, Astrid Gnekow, Olaf Witt, Hermann L. Mueller, Gabriele Calaminus, Gudrun Fleischhack, Uwe Kordes, Martin Mynarek, Stefan Rutkowski, Michael C. Fruehwald, Christof M. Kramm, Andreas von Deimling, Torsten Pietsch, Felix Sahm, Stefan M. Pfister, David. T. W. Jones
Summary: This study prospectively integrated DNA methylation profiling and targeted gene panel sequencing to evaluate their utility in routine neuropathology for newly diagnosed pediatric patients with CNS tumors. The integration of multi-omics improved diagnostic accuracy by refining DNA methylation classification, detecting relevant genetic alterations, and identifying cancer predisposition syndromes. Discrepancies between neuropathological classification and DNA methylation classification were particularly relevant for high-grade gliomas, and patients with lower-grade molecular profiles had improved survival.
Article
Oncology
Emily C. Hardin, Simone Schmid, Alexander Sommerkamp, Carina Bodden, Anna-Elisa Heipertz, Philipp Sievers, Andrea Wittmann, Till Milde, Stefan M. Pfister, Andreas von Deimling, Svea Horn, Nina A. Herz, Michele Simon, Ashwyn A. Perera, Amedeo Azizi, Ofelia Cruz, Sarah Curry, An Van Damme, Miklos Garami, Darren Hargrave, Antonis Kattamis, Barbara Faganel Kotnik, Paeivi Laehteenmaeki, Katrin Scheinemann, Antoinette Y. N. Schouten-van Meeteren, Astrid Sehested, Elisabetta Viscardi, Ole Mikal Wormdal, Michal Zapotocky, David S. Ziegler, Arend Koch, Pablo Hernaiz Driever, Olaf Witt, David Capper, Felix Sahm, David T. W. Jones, Cornelis M. van Tilburg
Summary: The addition of RNA-Seq to current diagnostic methods improves diagnostic accuracy, making precision oncology treatments more accessible for pediatric low-grade glioma (pLGG) patients. The study suggests including RNA-Seq as part of routine diagnostics, especially when no common pLGG alteration is identified.
Article
Multidisciplinary Sciences
Blair P. Bentley, Tomas Carrasco-Valenzuela, Elisa K. S. Ramos, Harvinder Pawar, Larissa Souza Arantes, Alana Alexander, Shreya M. Banerjee, Patrick Masterson, Martin Kuhlwilm, Martin Pippel, Jacquelyn Mountcastle, Bettina Haase, Marcela Uliano-Silva, Giulio Formenti, Kerstin Howe, William Chow, Alan Tracey, Ying Sims, Sarah Pelan, Jonathan Wood, Kelsey Yetsko, Justin R. Perrault, Kelly Stewart, Scott R. Benson, Yaniv Levy, Erica V. Todd, H. Bradley Shaffer, Peter Scott, Brian T. Henen, Robert W. Murphy, David W. Mohr, Alan F. Scott, David J. Duffy, Neil J. Gemmell, Alexander Suh, Sylke Winkler, Francoise Thibaud-Nissen, Mariana F. Nery, Tomas Marques-Bonet, Agostinho Antunes, Yaron Tikochinski, Peter H. Dutton, Olivier Fedrigo, Eugene W. Myers, Erich D. Jarvis, Camila J. Mazzoni, Lisa M. Komoroske
Summary: Sea turtles are ancient marine vertebrates that have evolved from terrestrial ancestors. Their unique physiological and ecological traits and the genomic basis behind them remain largely unknown. This study generated and analyzed high-quality reference genomes for leatherback and green turtles, revealing divergent evolution in certain gene families that may be responsible for immunological and sensory adaptations. Microchromosomes were found to play a critical role in vertebrate evolutionary adaptation. Furthermore, diversity and demographic histories differed significantly between the two species, indicating concerns over the persistence of leatherback turtles under future climate scenarios.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Neurosciences
Matthew Pun, Drew Pratt, Patricia R. Nano, Piyush K. Joshi, Li Jiang, Bernhard Englinger, Arvind Rao, Marcin Cieslik, Arul M. Chinnaiyan, Kenneth Aldape, Stefan Pfister, Mariella G. Filbin, Aparna Bhaduri, Sriram Venneti
Summary: Globally decreased H3K27me3 is a characteristic feature of H3K27-altered DMGs and PFAs. H3K27-altered DMGs are characterized by H3K27M mutations, while most PFAs overexpress EZHIP, which shares similarity with mutant H3K27M. H3K27M and EZHIP both inhibit the function of PRC2, responsible for H3K27me3 deposition.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2023)
Article
Biochemical Research Methods
Elias Ulrich, Stefan M. Pfister, Natalie Jaeger
Summary: As non-coding driver mutations become more important in cancer research, a comprehensive and user-friendly software solution for regulatory variant analysis and data visualization is highly relevant. A tool called Revana has been introduced, which can aggregate and visually represent regulatory variants from cancer genomes in a gene-centric manner. It requires whole-genome and RNA sequencing data of a tumor sample cohort and creates interactive HTML reports summarizing the most important regulatory events.
Article
Biochemical Research Methods
Sudeep Sahadevan, Thileepan Sekaran, Nadia Ashaf, Marko Fritz, Matthias W. Hentze, Wolfgang Huber, Thomas Schwarzl
Summary: Transcriptome-wide detection of binding sites of RNA-binding proteins can be achieved using Individual-nucleotide crosslinking and immunoprecipitation (iCLIP) and its derivative enhanced CLIP (eCLIP) sequencing methods. The python package htseq-clip is introduced for preprocessing, extracting, and summarizing crosslink site counts from i/eCLIP experimental data. The package provides crosslink site count matrices and other metrics for filtering and downstream analyses, such as the identification of differential binding sites.
Article
Biochemistry & Molecular Biology
Thomas Schwarzl, Sudeep Sahadevan, Benjamin Lang, Milad Miladi, Rolf Backofen, Wolfgang Huber, Matthias W. Hentze, Gian Gaetano Tartaglia
Summary: Enhanced crosslinking and immunoprecipitation sequencing (eCLIP-seq) is a method for detecting RNA-binding protein binding sites. However, current analysis strategies have low replication and high false positive rates. DEWSeq, a R/Bioconductor package, improves the detection of binding regions by utilizing replicate information and size-matched input controls. It has been shown to significantly increase the number and quality of binding sites.
NUCLEIC ACIDS RESEARCH
(2023)
