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| Item Type: | Article |
|---|---|
| Title: | AML with complex karyotype: extreme genomic complexity revealed by combined long-read sequencing and Hi-C technology |
| Creators Name: | Klever, M.K., Sträng, E., Hetzel, S., Jungnitsch, J., Dolnik, A., Schöpflin, R., Schrezenmeier, J.F.F., Schick, F., Blau, O., Westermann, J., Rücker, F.G., Xia, Z., Döhner, K., Schrezenmeier, H., Spielmann, M., Meissner, A., Melo, U.S., Mundlos, S. and Bullinger, L. |
| Abstract: | 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. |
| Keywords: | Abnormal Karyotype, Acute Myeloid Leukemia, Chromosome Aberrations, Genomics, Mutation, Ubiquitin-Specific Peptidase 7 |
| Source: | Blood Advances |
| ISSN: | 2473-9529 |
| Publisher: | American Society of Hematology |
| Volume: | 7 |
| Number: | 21 |
| Page Range: | 6520-6531 |
| Date: | 14 November 2023 |
| Official Publication: | https://doi.org/10.1182/bloodadvances.2023010887 |
| PubMed: | View item in PubMed |
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