Disrupting tRNA modifications to target mitochondrial vulnerabilities in drug-resistant leukemia cells
Abstract
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 antileukemic drugs. We identify the tRNA methyltransferase 5 (TRMT5)–mediated formation of N1-methylguanosine (m1G) in the transfer RNA (tRNA) anticodon loop as essential for mediating drug tolerance to cytarabine and venetoclax (Ven) 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 messenger RNA translation and oxidative phosphorylation, which are critical for sustaining drug tolerance in leukemia cells. This mitochondrial dependency correlates with therapy outcomes in patients with leukemia: lower expression of electron transport chain genes is linked to poorer outcomes in a cohort of nearly 100 patients with AML undergoing first induction therapy. Finally, we demonstrate that targeted depletion of the TRMT5 protein using a conditional degron, in conjunction with cytarabine and Ven treatment, synergistically induces cell death in drug-tolerant AML cells. Thus, our study reveals TRMT5 as a promising drug target for therapy-resistant leukemia.
Article Details
Authors (28)
Cornelius Pauli
7Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany
Michael Kienhöfer
1Division of Mechanisms Regulating Gene Expression, German Cancer Research Center, Heidelberg, Germany
Maximilian Felix Blank
2Medical Faculty Heidelberg and Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
Oguzhan Begik
Christian Rohde
1Department of Internal Medicine V, Hematology, Oncology, and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
Sarah Miriam Naomi Zimmermann
3Molecular Medicine Partnership Unit European Molecular Biology Laboratory–University Hospital Heidelberg, European Molecular Biology Laboratory, Heidelberg, Germany
Laura Werner
2Medical Faculty Heidelberg and Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
Daniel Heid
2Medical Faculty Heidelberg and Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
Fu Xu
Katharina Weidenauer
2Medical Faculty Heidelberg and Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
Sylvain Delaunay
Nadja Krall
1Division of Mechanisms Regulating Gene Expression, German Cancer Research Center, Heidelberg, Germany
Katrin Trunk
1Division of Mechanisms Regulating Gene Expression, German Cancer Research Center, Heidelberg, Germany
Duoduo Zhao
2Medical Faculty Heidelberg and Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
Fengbiao Zhou
2Medical Faculty Heidelberg and Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
Laia Llovera
5Epitranscriptomics and RNA Dynamics, Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain
Alexane Ollivier
5Epitranscriptomics and RNA Dynamics, Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain
Anke Heit-Mondrzyk
1Division of Mechanisms Regulating Gene Expression, German Cancer Research Center, Heidelberg, Germany
Uwe Platzbecker
Claudia Baldus
7Department of Hematology, Kiel University Hospital, Kiel, Germany
Hubert Serve
Martin Bornhäuser
Cathrine Broberg Vågbø
10Proteomics and Modomics Experimental Core Facility, Norwegian University of Science and Technology and St. Olavs Hospital, Trondheim, Norway
Salvador Aznar Benitah
Jeroen Krijgsveld
Eva Maria Novoa
Carsten Müller-Tidow
Michaela Frye
1Division of Mechanisms Regulating Gene Expression, German Cancer Research Center, Heidelberg, Germany