Initial leukemic epigenomic state determines hypomethylating agent response
Hypomethylating agents (HMAs) are a mainstay of therapy for myeloid cancers, but genetic biomarkers do not predict who will respond to treatment. Using a variety of single-cell sequencing approaches to define the epigenomic state of responder and nonresponder leukemic cells, we demonstrate that leukemic stem cells (LSC) exist in at least two different epigenomic states: a hematopoietic stem cell (HSC)-or multipotent progenitor (MPP)-like state that is sensitive to HMAs, independent of genetic mutations, or a lymphoid-primed MPP (LMPP)-like nonresponder state. Hypomethylation and chromatin accessibility at ZNF143- and CTCF-binding sites results in activation of HOXB4, which defines the HSC/MPP-like state and HMA-sensitivity. Our study provides evidence that the epigenomic state of the LSC is a major determinant of response to HMAs, and demonstrates that a routine clinical assay can identify patients who will respond. Current genetic biomarkers fail to predict responders to hypomethylating agents (HMAs) in myeloid cancers. Here, the authors employ a variety of single cell epigenomic assays to identify the epigenomic state of the leukemic stem cell, prior to therapy, as the determinant of HMA-responsiveness in myeloid malignancies.
Authors
- Brett Caswell
- Kieran O’Neill (ORCID: https://orcid.org/0000-0001-7609-5905)
- Franziska Mey (ORCID: https://orcid.org/0000-0002-3401-3235)
- Ryan J. Stubbins (ORCID: https://orcid.org/0000-0002-4718-5212)
- N N Medvedev
- Luca Malcovati (ORCID: https://orcid.org/0000-0002-1460-1611)
- Derek Tam
- Aly Karsan (ORCID: https://orcid.org/0000-0001-6753-892X)
- Aparna Gopal (ORCID: https://orcid.org/0000-0001-9757-9896)
- Franco J. Vizeacoumar
- Charles Craddock
- Frederick S Vizeacoumar
- Rena Buckstein
- Joshua Bridgers
- Yu Deng
- Jihong Jiang
- Mackenzie MacAuley
- Christina May (ORCID: https://orcid.org/0000-0003-2691-505X)
- Paresh Vyas (ORCID: https://orcid.org/0000-0003-3931-0914)
- Emilie Haniak
- Michael Heuser
- Michelle Moksa
- Martin Hirst (ORCID: https://orcid.org/0000-0001-9136-9054)
- Diana Lin (ORCID: https://orcid.org/0000-0001-9645-3247)
Institutions
- Sunnybrook Health Science Centre (CA)
- Vancouver Coastal Health (CA)
- University of British Columbia (CA)
- University of Pavia (IT)
- Queen Elizabeth Hospital Birmingham (GB)
- Spinal Cord Injury BC (CA)
- Health Sciences Centre (CA)
- University of Saskatchewan (CA)
- University of Oxford (GB)
- Saskatchewan Cancer Agency (CA)
- MRC Weatherall Institute of Molecular Medicine (GB)
- Canada's Michael Smith Genome Sciences Centre (CA)
- Policlinico San Matteo Fondazione (IT)
- Martin Luther University Halle-Wittenberg (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-05-22
- DOI
- https://doi.org/10.1038/s41467-026-73334-3
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- V Foundation for Cancer Research
- Terry Fox Research Institute
- Associazione Italiana per la Ricerca sul Cancro
- Canadian Cancer Society Research Institute