PMID- 37582288 OWN - NLM STAT- MEDLINE DCOM- 20231030 LR - 20231112 IS - 2473-9537 (Electronic) IS - 2473-9529 (Print) IS - 2473-9529 (Linking) VI - 7 IP - 21 DP - 2023 Nov 14 TI - AML with complex karyotype: extreme genomic complexity revealed by combined long-read sequencing and Hi-C technology. PG - 6520-6531 LID - 10.1182/bloodadvances.2023010887 [doi] AB - Acute myeloid leukemia with complex karyotype (CK-AML) is associated with poor prognosis, which is only in part explained by underlying TP53 mutations. Especially in the presence of complex chromosomal rearrangements, such as chromothripsis, the outcome of CK-AML is dismal. However, this degree of complexity of genomic rearrangements contributes to the leukemogenic phenotype and treatment resistance of CK-AML remains largely unknown. Applying an integrative workflow for the detection of structural variants (SVs) based on Oxford Nanopore (ONT) genomic DNA long-read sequencing (gDNA-LRS) and high-throughput chromosome confirmation capture (Hi-C) in a well-defined cohort of CK-AML identified regions with an extreme density of SVs. These rearrangements consisted to a large degree of focal amplifications enriched in the proximity of mammalian-wide interspersed repeat elements, which often result in oncogenic fusion transcripts, such as USP7::MVD, or the deregulation of oncogenic driver genes as confirmed by RNA-seq and ONT direct complementary DNA sequencing. We termed this novel phenomenon chromocataclysm. Thus, our integrative SV detection workflow combing gDNA-LRS and Hi-C enables to unravel complex genomic rearrangements at a very high resolution in regions hard to analyze by conventional sequencing technology, thereby providing an important tool to identify novel important drivers underlying cancer with complex karyotypic changes. CI - (c) 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. FAU - Klever, Marius-Konstantin AU - Klever MK AD - Division of Hematology, Oncology, and Cancer Immunology, Medical Department, Charite - Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health, Berlin, Germany. AD - RG Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany. AD - Institute for Medical Genetics and Human Genetics, Charite University Medicine Berlin, Berlin, Germany. FAU - Strang, Eric AU - Strang E AD - Division of Hematology, Oncology, and Cancer Immunology, Medical Department, Charite - Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health, Berlin, Germany. FAU - Hetzel, Sara AU - Hetzel S AUID- ORCID: 0000-0002-4783-3814 AD - Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany. FAU - Jungnitsch, Julius AU - Jungnitsch J AD - Institute for Medical Genetics and Human Genetics, Charite University Medicine Berlin, Berlin, Germany. AD - Human Molecular Genomics Group, Max Planck Institute for Molecular Genetics, Berlin, Germany. FAU - Dolnik, Anna AU - Dolnik A AD - Division of Hematology, Oncology, and Cancer Immunology, Medical Department, Charite - Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health, Berlin, Germany. FAU - Schopflin, Robert AU - Schopflin R AD - RG Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany. AD - Institute for Medical Genetics and Human Genetics, Charite University Medicine Berlin, Berlin, Germany. AD - Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany. FAU - Schrezenmeier, Jens-Florian AU - Schrezenmeier JF AD - Division of Hematology, Oncology, and Cancer Immunology, Medical Department, Charite - Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health, Berlin, Germany. FAU - Schick, Felix AU - Schick F AD - Division of Hematology, Oncology, and Cancer Immunology, Medical Department, Charite - Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health, Berlin, Germany. FAU - Blau, Olga AU - Blau O AD - Division of Hematology, Oncology, and Cancer Immunology, Medical Department, Charite - Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health, Berlin, Germany. AD - Labor Berlin - Charite Vivantes GmbH, Berlin, Germany. FAU - Westermann, Jorg AU - Westermann J AD - Division of Hematology, Oncology, and Cancer Immunology, Medical Department, Charite - Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health, Berlin, Germany. AD - Labor Berlin - Charite Vivantes GmbH, Berlin, Germany. FAU - Rucker, Frank G AU - Rucker FG AD - Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany. FAU - Xia, Zuyao AU - Xia Z AD - Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany. FAU - Dohner, Konstanze AU - Dohner K AD - Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany. FAU - Schrezenmeier, Hubert AU - Schrezenmeier H AD - Institute of Transfusion Medicine, University of Ulm, Ulm, Germany. AD - Institute for Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service Baden-Wurttemberg-Hessen and University Hospital Ulm, Ulm, Germany. FAU - Spielmann, Malte AU - Spielmann M AUID- ORCID: 0000-0002-0583-4683 AD - Human Molecular Genomics Group, Max Planck Institute for Molecular Genetics, Berlin, Germany. AD - Institut fur Humangenetik Lubeck, Universitat zu Lubeck, Lubeck, Germany. FAU - Meissner, Alexander AU - Meissner A AUID- ORCID: 0000-0001-8646-7469 AD - Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany. FAU - Melo, Uira Souto AU - Melo US AD - RG Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany. AD - Institute for Medical Genetics and Human Genetics, Charite University Medicine Berlin, Berlin, Germany. FAU - Mundlos, Stefan AU - Mundlos S AD - RG Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany. AD - Institute for Medical Genetics and Human Genetics, Charite University Medicine Berlin, Berlin, Germany. AD - Labor Berlin - Charite Vivantes GmbH, Berlin, Germany. FAU - Bullinger, Lars AU - Bullinger L AD - Division of Hematology, Oncology, and Cancer Immunology, Medical Department, Charite - Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health, Berlin, Germany. AD - Labor Berlin - Charite Vivantes GmbH, Berlin, Germany. AD - German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Blood Adv JT - Blood advances JID - 101698425 RN - EC 3.4.19.12 (USP7 protein, human) RN - EC 3.4.19.12 (Ubiquitin-Specific Peptidase 7) SB - IM MH - Humans MH - *Leukemia, Myeloid, Acute/diagnosis/genetics/therapy MH - Abnormal Karyotype MH - Chromosome Aberrations MH - Mutation MH - Genomics MH - Ubiquitin-Specific Peptidase 7/genetics PMC - PMC10632680 COIS- Conflict-of-interest disclosure: L.B. has advisory role in AbbVie, Amgen, Astellas, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Gilead, Hexal, Janssen, Jazz Pharmaceuticals, Menarini, Novartis, Pfizer, Sanofi, and Seattle Genetics; and receives research funding from Bayer and Jazz Pharmaceuticals. The remaining authors declare no competing financial interests. EDAT- 2023/08/15 18:42 MHDA- 2023/10/30 06:46 PMCR- 2023/08/17 CRDT- 2023/08/15 17:13 PHST- 2023/07/30 00:00 [accepted] PHST- 2023/06/05 00:00 [received] PHST- 2023/10/30 06:46 [medline] PHST- 2023/08/15 18:42 [pubmed] PHST- 2023/08/15 17:13 [entrez] PHST- 2023/08/17 00:00 [pmc-release] AID - 497453 [pii] AID - 10.1182/bloodadvances.2023010887 [doi] PST - ppublish SO - Blood Adv. 2023 Nov 14;7(21):6520-6531. doi: 10.1182/bloodadvances.2023010887.