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Peer-reviewedCC BYScience Advances

TET2-driven activation of AGO2 links epigenetic remodeling to myeloid commitment and leukemia

  • Aleksey Lazarenkov1
  • Gemma Valcárcel1
  • Alba Martinez2,3
  • Clara Berenguer1,4
  • Anna V. López-Rubio1
  • Mireia Obiols1
  • Claudia Fontanet1
  • Ana Barba1
  • Juan José Rodríguez-Sevilla5,6
  • Gregoire Stik7
  • Irmela Jeremias8,9
  • Pablo Menendez2,3,10,11,12,13
1 more authors
  • José Luis Sardina1
13 affiliations
  1. 1Epigenetic Control of Haematopoiesis Group, Josep Carreras Leukaemia Research Institute (IJC), Campus Can Ruti, Badalona, Spain.
  2. 2Stem Cell Biology, Developmental Leukemia and Immunotherapy Group, Josep Carreras Leukaemia Research Institute (IJC), Campus Hospital Clínic, Barcelona, Spain.
  3. 3Red de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, Madrid, Spain.
  4. 4Endocrine Regulatory Genomics, Department of Experimental & Health Sciences, University Pompeu Fabra, 08003 Barcelona, Spain.
  5. 5Department of Hematology, Hospital Clinic Barcelona, Barcelona, Spain.
  6. 6Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
  7. 7Nuclear Architecture in Leukemia Group, Josep Carreras Leukaemia Research Institute (IJC), Campus Can Ruti, Badalona, Spain.
  8. 8Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Munich, German Research Center for Environmental Health (HMGU), Munich, Germany.
  9. 9German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and University Hospital LMU Munich, Munich, Germany.
  10. 10Pediatric Cancer Centre Barcelona-Institut de Recerca Sant Joan de Deu (PCCB-SJD), Barcelona, Spain.
  11. 11Department of Biomedicine, University of Barcelona, Barcelona, Spain.
  12. 12Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
  13. 13Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
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Abstract

DNA methylation dynamics shape hematopoietic differentiation and leukemogenesis, yet how the dioxygenase TET2-frequently mutated in myeloid malignancies-directs lineage-specific regulatory programs remains unclear. Here, we integrated DNA methylation, chromatin accessibility, three-dimensional (3D) genome architecture, transcriptional profiling, and TET2 chromatin occupancy to define TET2-dependent control of human myeloid commitment. We found that TET2-bound regulatory regions gain short- and long-range chromatin interactions and that a distinct subset of distal, enhancer-enriched sites undergoes TET2-driven demethylation and activation. Among these, we identified and functionally validated an AGO2 myeloid-specific intragenic enhancer that is frequently hypermethylated in patients with TET2-mutant acute myeloid leukemia. AGO2 expression stratifies patient survival, and AGO2 depletion abrogates leukemic engraftment in vivo. These findings uncover a TET2-AGO2 regulatory axis that integrates epigenetic remodeling, 3D genome reorganization, and leukemic fitness, and they highlight AGO2 as a potential biomarker and therapeutic target in myeloid leukemia.

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Cite

BibTeXRIS
BibTeX
@article{lazarenkov2026tet2driven,
  title = {{TET2-driven activation of AGO2 links epigenetic remodeling to myeloid commitment and leukemia}},
  author = {Aleksey Lazarenkov and Gemma Valcárcel and Alba Martinez and Clara Berenguer and Anna V. López-Rubio and Mireia Obiols and Claudia Fontanet and Ana Barba and Juan José Rodríguez-Sevilla and Gregoire Stik and Irmela Jeremias and Pablo Menendez and José Luis Sardina},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aee5701},
  url = {https://www.science.org/doi/10.1126/sciadv.aee5701},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - TET2-driven activation of AGO2 links epigenetic remodeling to myeloid commitment and leukemia
AU  - Aleksey Lazarenkov
AU  - Gemma Valcárcel
AU  - Alba Martinez
AU  - Clara Berenguer
AU  - Anna V. López-Rubio
AU  - Mireia Obiols
AU  - Claudia Fontanet
AU  - Ana Barba
AU  - Juan José Rodríguez-Sevilla
AU  - Gregoire Stik
AU  - Irmela Jeremias
AU  - Pablo Menendez
AU  - José Luis Sardina
PY  - 2026
DA  - 2026/10/23
JO  - Science Advances
DO  - 10.1126/sciadv.aee5701
UR  - https://www.science.org/doi/10.1126/sciadv.aee5701
AB  - DNA methylation dynamics shape hematopoietic differentiation and leukemogenesis, yet how the dioxygenase TET2-frequently mutated in myeloid malignancies-directs lineage-specific regulatory programs remains unclear. Here, we integrated DNA methylation, chromatin accessibility, three-dimensional (3D) genome architecture, transcriptional profiling, and TET2 chromatin occupancy to define TET2-dependent control of human myeloid commitment. We found that TET2-bound regulatory regions gain short- and long-range chromatin interactions and that a distinct subset of distal, enhancer-enriched sites undergoes TET2-driven demethylation and activation. Among these, we identified and functionally validated an AGO2 myeloid-specific intragenic enhancer that is frequently hypermethylated in patients with TET2-mutant acute myeloid leukemia. AGO2 expression stratifies patient survival, and AGO2 depletion abrogates leukemic engraftment in vivo. These findings uncover a TET2-AGO2 regulatory axis that integrates epigenetic remodeling, 3D genome reorganization, and leukemic fitness, and they highlight AGO2 as a potential biomarker and therapeutic target in myeloid leukemia.
SN  - 2375-2548
ER  -