Targeting Artemis sensitizes acute lymphoblastic leukemia cells to topoisomerase 2 poisons by disrupting DNA-PKcs-dependent repair.
10 affiliations
- 1Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, Irvine, CA, USA.
- 2Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA.
- 3Institute for Immunology, University of California, Irvine, Irvine, CA, USA.
- 4Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA, USA.
- 5Graduate School of Nanobioscience, Yokohama City University, Yokohama, Japan.
- 6Department of Microbiology, Genetics, and Immunology, Michigan State University, East Lansing, MI, USA.
- 7Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, Irvine, CA, USA. [email protected].
- 8Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA. [email protected].
- 9Institute for Immunology, University of California, Irvine, Irvine, CA, USA. [email protected].
- 10Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA, USA. [email protected].
Abstract
Topoisomerase 2 (Top2) poisons are widely used in cancer therapy but are associated with toxicity and secondary malignancies. Top2 adduct removal requires endonuclease activity prior to repair of the resulting DNA double-strand break (DSB). We show that the non-homologous end joining (NHEJ) enzyme Artemis is a key player in the process and a major target for treatment of human B-cell acute lymphoblastic leukemia (ALL). An Artemis knockout is sensitive to etoposide treatment at nanomolar levels and has significantly more unrepaired DNA DSBs. Inhibition of the Artemis activator, DNA-dependent Protein Kinase Catalytic Subunit (DNA-PKcs), acts synergistically with Top2 poisons to further sensitize ALL cells. Genetic loss of Artemis ablates this synergy underscoring its critical role in this drug interaction. Furthermore, Artemis loss results in a significant accumulation of covalent Top2A DNA adducts following etoposide treatment and a significant increase in unrepaired DNA DSBs. As clinical data demonstrate that high Artemis expression correlates with poor survival in several cancers, our work may unlock new avenues for the treatment of aggressive cancers.
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BibTeX
@article{folkerts2026targeting,
title = {{Targeting Artemis sensitizes acute lymphoblastic leukemia cells to topoisomerase 2 poisons by disrupting DNA-PKcs-dependent repair.}},
author = {Melissa L Folkerts and Cameron Hom and Angie T M Nguyen and Kaiyuan V Shen and Alyssa M Monterroso and Ellianna M Damozonio and Alejandra Aguilar-Quintero and Valeria Rangel and Pedro Ortega and Selma Masri and Noritaka Adachi and Rémi Buisson and Katheryn Meek and Nicholas R Pannunzio},
journal = {Communications biology},
year = {2026},
month = aug,
doi = {10.1038/s42003-026-10731-w},
url = {https://europepmc.org/article/MED/42919848},
note = {CC BY},
}
RIS
TY - JOUR
TI - Targeting Artemis sensitizes acute lymphoblastic leukemia cells to topoisomerase 2 poisons by disrupting DNA-PKcs-dependent repair.
AU - Melissa L Folkerts
AU - Cameron Hom
AU - Angie T M Nguyen
AU - Kaiyuan V Shen
AU - Alyssa M Monterroso
AU - Ellianna M Damozonio
AU - Alejandra Aguilar-Quintero
AU - Valeria Rangel
AU - Pedro Ortega
AU - Selma Masri
AU - Noritaka Adachi
AU - Rémi Buisson
AU - Katheryn Meek
AU - Nicholas R Pannunzio
PY - 2026
DA - 2026/08/01
JO - Communications biology
DO - 10.1038/s42003-026-10731-w
UR - https://europepmc.org/article/MED/42919848
AB - Topoisomerase 2 (Top2) poisons are widely used in cancer therapy but are associated with toxicity and secondary malignancies. Top2 adduct removal requires endonuclease activity prior to repair of the resulting DNA double-strand break (DSB). We show that the non-homologous end joining (NHEJ) enzyme Artemis is a key player in the process and a major target for treatment of human B-cell acute lymphoblastic leukemia (ALL). An Artemis knockout is sensitive to etoposide treatment at nanomolar levels and has significantly more unrepaired DNA DSBs. Inhibition of the Artemis activator, DNA-dependent Protein Kinase Catalytic Subunit (DNA-PKcs), acts synergistically with Top2 poisons to further sensitize ALL cells. Genetic loss of Artemis ablates this synergy underscoring its critical role in this drug interaction. Furthermore, Artemis loss results in a significant accumulation of covalent Top2A DNA adducts following etoposide treatment and a significant increase in unrepaired DNA DSBs. As clinical data demonstrate that high Artemis expression correlates with poor survival in several cancers, our work may unlock new avenues for the treatment of aggressive cancers.
SN - 2399-3642
ER -