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@ARTICLE{Klever:285056,
author = {M.-K. Klever and E. Sträng and S. Hetzel and J. Jungnitsch
and A. Dolnik and R. Schöpflin and J.-F. Schrezenmeier and
F. Schick and O. Blau and J. Westermann and F. G. Rücker
and Z. Xia and K. Döhner and H. Schrezenmeier and M.
Spielmann and A. Meissner and U. S. Melo and S. Mundlos and
L. Bullinger$^*$},
title = {{AML} with complex karyotype: extreme genomic complexity
revealed by combined long-read sequencing and {H}i-{C}
technology.},
journal = {Blood advances},
volume = {7},
number = {21},
issn = {2473-9529},
address = {Washington, DC},
publisher = {American Society of Hematology},
reportid = {DKFZ-2023-02199},
pages = {6520 - 6531},
year = {2023},
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 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.},
keywords = {Humans / Leukemia, Myeloid, Acute: diagnosis / Leukemia,
Myeloid, Acute: genetics / Leukemia, Myeloid, Acute: therapy
/ Abnormal Karyotype / Chromosome Aberrations / Mutation /
Genomics / Ubiquitin-Specific Peptidase 7: genetics / USP7
protein, human (NLM Chemicals) / Ubiquitin-Specific
Peptidase 7 (NLM Chemicals)},
cin = {BE01},
ddc = {610},
cid = {I:(DE-He78)BE01-20160331},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:37582288},
doi = {10.1182/bloodadvances.2023010887},
url = {https://inrepo02.dkfz.de/record/285056},
}