DOI: 10.1182/bloodadvances.2023010887 ISSN:

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 F Schrezenmeier, Felix Schick, Olga Blau, Jörg Westermann, Frank G. Rücker, Zuyao Xia, Konstanze Döhner, Hubert Schrezenmeier, Malte Spielmann, Alexander Meissner, Uira Souto Melo, Stefan Mundlos, Lars Bullinger
  • Hematology

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 (MIR) 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 cDNA 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.

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