DOT1L provides transcriptional memory through PRC1.1 antagonism
DOT1L and Menin are essential cofactors for the oncogenic activity of MLL fusion proteins (MLL-FPs) in leukaemia. However, the mechanisms underpinning the therapeutic effects of their inhibitors remain unclear. Here we identify a critical role for the non-canonical Polycomb repressive complex 1.1 (PRC1.1) in mediating the cellular responses to DOT1L and Menin inhibitors. Menin inhibition induces PRC1.1-dependent deposition of H2AK119ub to silence a subset of MLL-FP targets, whereas DOT1L inhibition results in a genome-wide increase in H2AK119ub. We show that enhanced PRC1.1 activity arises specifically from the progressive loss of DOT1L-mediated H3K79 methylation, independent of MLL-FP displacement or transcriptional repression. This regulatory crosstalk is conserved across cell types and is driven by direct biochemical antagonism between H3K79 methylation and PRC1 activity. Together, our findings establish DOT1L as a component of transcriptional memory co-opted in leukaemia and suggest it serves as the missing link balancing the opposing forces of the MLL-Polycomb axis.
Authors
- Kathy Knezevic (ORCID: https://orcid.org/0000-0002-3940-3363)
- Olivia G. Dobbs (ORCID: https://orcid.org/0000-0003-4710-9401)
- Chen Davidovich
- Omer Gilan (ORCID: https://orcid.org/0000-0003-4156-2619)
- Stephen C Suits (ORCID: https://orcid.org/0000-0003-3231-4429)
- Vita Levina (ORCID: https://orcid.org/0000-0003-2850-9389)
- Michael Uckelmann (ORCID: https://orcid.org/0000-0002-4370-6009)
- Andrew C. Perkins (ORCID: https://orcid.org/0000-0003-3644-7093)
- Enid Y. N. Lam
- Charles C. Bell (ORCID: https://orcid.org/0000-0003-2194-8311)
- Emily Heikamp (ORCID: https://orcid.org/0000-0002-4591-4477)
- Laure Talarmain
- Scott A. Armstrong
- James J. The
- Zhihao Lai
- Daniel T. Ferguson
- Bradon Rumler
- Charlene Lam
- Graham W. Magor
- Daniel Neville
- Shania Alex
Institutions
- Boston Children's Hospital (US)
- Harvard University (US)
- The University of Queensland (AU)
- The University of Melbourne (AU)
- QIMR Berghofer Medical Research Institute (AU)
- Discovery Institute (US)
- Peter MacCallum Cancer Centre (AU)
- Monash Medical Centre (AU)
- Mater Research (AU)
- Dana-Farber Cancer Institute (US)
- Monash University (AU)
Publication Details
- Journal
- Nature Cell Biology
- Published
- 2026-02-01
- DOI
- https://doi.org/10.1038/s41556-025-01859-8
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 0.00