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@ARTICLE{Darzentas:275799,
      author       = {F. Darzentas and M. Szczepanowski and M. Kotrová and A.
                      Hartmann and T. Beder and N. Gökbuget and S. Schwartz$^*$
                      and L. Bastian and C. D. Baldus and K. Pál and N. Darzentas
                      and M. Brüggemann},
      title        = {{I}nsights into {IGH} clonal evolution in {BCP}-{ALL}:
                      frequency, mechanisms, associations, and diagnostic
                      implications.},
      journal      = {Frontiers in immunology},
      volume       = {14},
      issn         = {1664-3224},
      address      = {Lausanne},
      publisher    = {Frontiers Media},
      reportid     = {DKFZ-2023-00887},
      pages        = {1125017},
      year         = {2023},
      abstract     = {The malignant transformation leading to a maturation arrest
                      in B-cell precursor acute lymphoblastic leukemia (BCP-ALL)
                      occurs early in B-cell development, in a pro-B or pre-B
                      cell, when somatic recombination of variable (V), diversity
                      (D), and joining (J) segment immunoglobulin (IG) genes and
                      the B-cell rescue mechanism of VH replacement might be
                      ongoing or fully active, driving clonal evolution. In this
                      study of newly diagnosed BCP-ALL, we sought to understand
                      the mechanistic details of oligoclonal composition of the
                      leukemia at diagnosis, clonal evolution during follow-up,
                      and clonal distribution in different hematopoietic
                      compartments.Utilizing high-throughput sequencing assays and
                      bespoke bioinformatics we identified BCP-ALL-derived
                      clonally-related IGH sequences by their shared 'DNJ-stem'.We
                      introduce the concept of 'marker DNJ-stem' to cover the
                      entirety of, even lowly abundant, clonally-related family
                      members. In a cohort of 280 adult patients with BCP-ALL, IGH
                      clonal evolution at diagnosis was identified in one-third of
                      patients. The phenomenon was linked to contemporaneous
                      recombinant and editing activity driven by aberrant ongoing
                      DH/VH-DJH recombination and VH replacement, and we share
                      insights and examples for both. Furthermore, in a subset of
                      167 patients with molecular subtype allocation, high
                      prevalence and high degree of clonal evolution driven by
                      ongoing DH/VH-DJH recombination were associated with the
                      presence of KMT2A gene rearrangements, while VH replacements
                      occurred more frequently in Ph-like and DUX4 BCP-ALL.
                      Analysis of 46 matched diagnostic bone marrow and peripheral
                      blood samples showed a comparable clonal and clonotypic
                      distribution in both hematopoietic compartments, but the
                      clonotypic composition markedly changed in longitudinal
                      follow-up analysis in select cases. Thus, finally, we
                      present cases where the specific dynamics of clonal
                      evolution have implications for both the initial marker
                      identification and the MRD monitoring in follow-up
                      samples.Consequently, we suggest to follow the marker
                      DNJ-stem (capturing all family members) rather than specific
                      clonotypes as the MRD target, as well as to follow both VDJH
                      and DJH family members since their respective kinetics are
                      not always parallel. Our study further highlights the
                      intricacy, importance, and present and future challenges of
                      IGH clonal evolution in BCP-ALL.},
      keywords     = {DNJ-stem (Other) / IGH rearrangements (Other) / VH
                      replacement (Other) / acute lymphoblastic leukemia (Other) /
                      clonal evolution (Other) / high-throughput sequencing
                      (Other) / minimal residual disease (Other)},
      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:37143651},
      pmc          = {pmc:PMC10151743},
      doi          = {10.3389/fimmu.2023.1125017},
      url          = {https://inrepo02.dkfz.de/record/275799},
}