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@ARTICLE{Jepsen:300277,
      author       = {V. H. Jepsen$^*$ and A. Hanel and D. J. Picard$^*$ and R.
                      Bhave and R. Hasselmann$^*$ and J. Mehtonen and J.
                      Schliehe-Diecks$^*$ and C.-J. Kath$^*$ and V. Suppiyar$^*$
                      and Y. Prasad$^*$ and K. Schaal$^*$ and J.-W. Tu$^*$ and N.
                      Rüchel$^*$ and E. Kameri$^*$ and N. Qin$^*$ and H. Wang and
                      Z. Zhuang and R. Wagener$^*$ and L. Blümel$^*$ and T.
                      Lautwein and D. Hein$^*$ and D. Koppstein$^*$ and G. Kögler
                      and M. Remke$^*$ and S. Bhatia$^*$ and M. Heinäniemi and A.
                      Borkhardt$^*$ and U. Fischer$^*$},
      title        = {{H}1-0 is a specific mediator of the repressive
                      {ETV}6::{RUNX}1 transcriptional landscape in preleukemia and
                      {B} cell acute lymphoblastic leukemia.},
      journal      = {HemaSphere},
      volume       = {9},
      number       = {4},
      issn         = {2572-9241},
      address      = {Hoboken},
      publisher    = {John Wiley $\&$ Sons Ltd.},
      reportid     = {DKFZ-2025-00730},
      pages        = {e70116},
      year         = {2025},
      abstract     = {ETV6::RUNX1, the most common oncogenic fusion in pediatric
                      B cell precursor acute lymphoblastic leukemia (BCP-ALL),
                      induces a clinically silent preleukemic state that can
                      persist in carriers for over a decade and may progress to
                      overt leukemia upon acquisition of secondary lesions. The
                      mechanisms contributing to quiescence of ETV6::RUNX1+
                      preleukemic cells still remain elusive. In this study, we
                      identify linker histone H1-0 as a critical mediator of the
                      ETV6::RUNX1+ preleukemic state by employing human -induced
                      pluripotent stem cell (hiPSC) models engineered by using
                      CRISPR/Cas9 gene editing. Global gene expression analysis
                      revealed upregulation of H1-0 in ETV6::RUNX1+ hiPSCs that
                      was preserved upon hematopoietic differentiation. Moreover,
                      whole transcriptome data of 1,727 leukemia patient samples
                      showed significantly elevated H1-0 levels in ETV6::RUNX1+
                      BCP-ALL compared to other leukemia entities. Using
                      dual-luciferase promoter assays, we show that ETV6::RUNX1
                      induces H1-0 promoter activity. We further demonstrate that
                      depletion of H1-0 specifically inhibits ETV6::RUNX1
                      signature genes, including RAG1 and EPOR. Single-cell
                      sequencing showed that H1-0 is highly expressed in quiescent
                      hematopoietic cells. Importantly, H1-0 protein levels
                      correspond to susceptibility of BCP-ALL cells towards
                      histone deacetylase inhibitors (HDACis) and combinatorial
                      treatment using the H1-0-inducing HDACi Quisinostat showed
                      promising synergism with established chemotherapeutic drugs.
                      Taken together, our data identify H1-0 as a key regulator of
                      the ETV6::RUNX1+ transcriptome and indicate that the
                      addition of Quisinostat may be beneficial to target
                      non-responsive or relapsing ETV6::RUNX1+ BCP-ALL.},
      cin          = {ED01},
      ddc          = {610},
      cid          = {I:(DE-He78)ED01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40177616},
      pmc          = {pmc:PMC11962653},
      doi          = {10.1002/hem3.70116},
      url          = {https://inrepo02.dkfz.de/record/300277},
}