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@ARTICLE{Auer:301499,
      author       = {F. Auer and M. N. F. Morcos and M. Sipola and I. Akhtar and
                      S. Moisio and J. Vogt and R. Haag and M. Lahnalampi and T.
                      J. Tuononen and A. Hanel and A. Viitasalo and U. A.
                      Friedrich and A. Dahl and C. Prexler and A. A. Pandyra and
                      P. Stepensky and M. Takagi and A. Borkhardt and M.
                      Heinäniemi and J. Hauer$^*$},
      title        = {{T}rajectories from single-cells to {PAX}5-driven leukemia
                      reveal {PAX}5-{MYC} interplay in vivo.},
      journal      = {Leukemia},
      volume       = {39},
      number       = {7},
      issn         = {0887-6924},
      address      = {London},
      publisher    = {Springer Nature},
      reportid     = {DKFZ-2025-01038},
      pages        = {1607-1626},
      year         = {2025},
      note         = {2025 Jul;39(7):1607-1626},
      abstract     = {PAX5 acts as a master regulator of B-cell proliferation and
                      differentiation. Its germline and somatic deregulation have
                      both been implicated in the development of B-cell precursor
                      acute lymphoblastic leukemia (BCP-ALL). However, the process
                      how reduced PAX5 transcriptional activity mediates
                      progression to BCP-ALL, is still poorly understood. Here, we
                      characterized the longitudinal effects of PAX5 reduction on
                      healthy, pre-leukemic and BCP-ALL cells at the single-cell
                      level. Cell-surface marker analysis revealed a
                      genotype-driven enrichment of the pre-BII population in
                      healthy Pax5± mice. This population showed downregulated
                      B-cell receptor signaling, while DNA replication/repair and
                      cell-cycle signaling pathways were upregulated. Moreover, we
                      observed a shift in the kappa/lambda light chain ratio
                      toward lambda rearranged B-cells. Transplantation
                      experiments further validated a delay of Pax5± pre-BII
                      cells in maturation and transition to IgM-positivity.
                      Additionally, single-cell RNA-Sequencing and bulk
                      ATAC-Sequencing of different stages of BCP-ALL evolution
                      showed that Pax5± pre-leukemic cells lose their B-cell
                      identity and display Myc activation. Subsequently, BCP-ALLs
                      acquired additional RAG-mediated aberrations and driver
                      mutations in JAK-STAT and RAS-signaling pathways. Together,
                      this study elucidates molecular and functional checkpoints
                      in PAX5-mediated pre-leukemic cell progression exploitable
                      for therapeutic intervention and demonstrates that PAX5
                      reduction is sufficient to initiate clonal evolution to
                      BCP-ALL through activation of MYC.},
      cin          = {MU01},
      ddc          = {610},
      cid          = {I:(DE-He78)MU01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40394211},
      doi          = {10.1038/s41375-025-02626-2},
      url          = {https://inrepo02.dkfz.de/record/301499},
}