AML with complex karyotype: extreme genomic complexity revealed by combined long-read sequencing and Hi-C technology

Marius Konstantin Klever, Eric Sträng, Sara Hetzel, Julius Jungnitsch, Anna Dolnik, Robert Schöpflin, Jens Florian Schrezenmeier, Felix Schick, Olga Blau, Jörg Westermann, Frank G. Rücker, Zuyao Xia, Konstanze Döhner, Hubert Schrezenmeier, Malte Spielmann, Alexander Meissner, Uirá Souto Melo, Stefan Mundlos*, Lars Bullinger*

*Corresponding author for this work


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.

Original languageEnglish
JournalBlood Advances
Issue number21
Pages (from-to)6520-6531
Number of pages12
Publication statusPublished - 2023

Research Areas and Centers

  • Research Area: Medical Genetics

DFG Research Classification Scheme

  • 205-03 Human Genetics
  • 201-05 General Genetics and Functional Genomics
  • 206-06 Molecular and Cellular Neurology and Neuropathology

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