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@ARTICLE{Pauli:305504,
      author       = {C. Pauli$^*$ and M. Kienhöfer$^*$ and M. Blank$^*$ and O.
                      Begik and C. Rohde and S. Zimmermann$^*$ and L. Werner and
                      D. Heid and F. Xu$^*$ and K. Weidenauer and S. Delaunay$^*$
                      and N. K. Krall$^*$ and K. Trunk$^*$ and D. Zhao and F. Zhou
                      and L. Llovera and O. Alexane and A. Heit-Mondrzyk$^*$ and
                      U. Platzbecker and C. D. Baldus and H. Serve and M.
                      Bornhäuser and C. B. Vågbø and S. A. Benitah and J.
                      Krijgsveld$^*$ and E. M. Novoa and C. Müller-Tidow and M.
                      Frye$^*$},
      title        = {{D}isrupting t{RNA} modifications to target mitochondrial
                      vulnerabilities in drug-resistant leukemia cells.},
      journal      = {Blood},
      volume       = {nn},
      issn         = {0006-4971},
      address      = {Washington, DC},
      publisher    = {American Society of Hematology},
      reportid     = {DKFZ-2025-02191},
      pages        = {nn},
      year         = {2025},
      note         = {#EA:A350#LA:A350# / epub},
      abstract     = {Dysregulated RNA modifications contribute to cancer
                      progression and therapy resistance, yet the underlying
                      mechanism often remains unknown. Here, we perform
                      CRISPR-based synthetic lethality screens to systematically
                      explore the role of RNA modifications in mediating
                      resistance to anti-leukaemic drugs. We identify the
                      TRMT5-mediated formation of N1-methylguanosine (m1G) in the
                      tRNA anticodon loop as essential for mediating drug
                      tolerance to cytarabine and venetoclax in acute myeloid
                      leukemia (AML). TRMT5 methylates nearly all mitochondrial
                      and nuclear tRNAs with a guanosine at position 37, but its
                      role in promoting drug tolerance specifically depends on its
                      mitochondrial function. TRMT5 is essential for the dynamic
                      upregulation of mitochondrial mRNA translation and oxidative
                      phosphorylation (OXPHOS), which are critical for sustaining
                      drug tolerance in leukemia cells. This mitochondrial
                      dependency correlates with therapy outcomes in leukemia
                      patients: lower expression of electron transport chain genes
                      is linked to poorer outcomes in a cohort of nearly 100 AML
                      patients undergoing first induction therapy. Finally, we
                      demonstrate that targeted depletion of TRMT5 protein using a
                      conditional degron, in conjunction with cytarabine and
                      venetoclax treatment, synergistically induces cell death in
                      drug-tolerant AML cells. Thus, our study reveals TRMT5 as
                      promising drug target for therapy-resistant leukemia.},
      cin          = {A350 / B230},
      ddc          = {610},
      cid          = {I:(DE-He78)A350-20160331 / I:(DE-He78)B230-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40749163},
      doi          = {10.1182/blood.2024027822},
      url          = {https://inrepo02.dkfz.de/record/305504},
}