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@ARTICLE{Lepp:294687,
      author       = {A.-M. Leppä$^*$ and K. Grimes and H. Jeong and F. Y.
                      Huang$^*$ and A. Andrades and A. Waclawiczek$^*$ and T. Boch
                      and A. Jauch and S. Renders$^*$ and P. Stelmach$^*$ and C.
                      Müller-Tidow and D. Karpova$^*$ and M. Sohn$^*$ and F.
                      Grünschläger$^*$ and P. Hasenfeld and E. Benito Garagorri
                      and V. Thiel$^*$ and A. Dolnik and B. Rodriguez-Martin and
                      L. Bullinger and K. Mrózek and A.-K. Eisfeld and A.
                      Krämer$^*$ and A. D. Sanders and J. Korbel$^*$ and A.
                      Trumpp$^*$},
      title        = {{S}ingle-cell multiomics analysis reveals dynamic clonal
                      evolution and targetable phenotypes in acute myeloid
                      leukemia with complex karyotype.},
      journal      = {Nature genetics},
      volume       = {56},
      number       = {12},
      issn         = {1061-4036},
      address      = {London},
      publisher    = {Macmillan Publishers Limited, part of Springer Nature},
      reportid     = {DKFZ-2024-02422},
      pages        = {2790-2803},
      year         = {2024},
      note         = {DKFZ-ZMBH Alliance / #EA:A010#LA:A010#LA:B480# / 2024
                      Dec;56(12):2790-2803},
      abstract     = {Chromosomal instability is a major driver of intratumoral
                      heterogeneity (ITH), promoting tumor progression. In the
                      present study, we combined structural variant discovery and
                      nucleosome occupancy profiling with transcriptomic and
                      immunophenotypic changes in single cells to study ITH in
                      complex karyotype acute myeloid leukemia (CK-AML). We
                      observed complex structural variant landscapes within
                      individual cells of patients with CK-AML characterized by
                      linear and circular breakage-fusion-bridge cycles and
                      chromothripsis. We identified three clonal evolution
                      patterns in diagnosis or salvage CK-AML (monoclonal, linear
                      and branched polyclonal), with $75\%$ harboring multiple
                      subclones that frequently displayed ongoing karyotype
                      remodeling. Using patient-derived xenografts, we
                      demonstrated varied clonal evolution of leukemic stem cells
                      (LSCs) and further dissected subclone-specific drug-response
                      profiles to identify LSC-targeting therapies, including
                      BCL-xL inhibition. In paired longitudinal patient samples,
                      we further revealed genetic evolution and cell-type
                      plasticity as mechanisms of disease progression. By
                      dissecting dynamic genomic, phenotypic and functional
                      complexity of CK-AML, our findings offer clinically relevant
                      avenues for characterizing and targeting disease-driving
                      LSCs.},
      cin          = {A010 / A360 / B480 / HD01},
      ddc          = {570},
      cid          = {I:(DE-He78)A010-20160331 / I:(DE-He78)A360-20160331 /
                      I:(DE-He78)B480-20160331 / I:(DE-He78)HD01-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39587361},
      doi          = {10.1038/s41588-024-01999-x},
      url          = {https://inrepo02.dkfz.de/record/294687},
}