Initial leukemic epigenomic state determines hypomethylating agent response
Year: 2026
Type: article
Abstract: 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.
Source: Nature Communications
Authors: Aparna Gopal, Derek Tam, Franziska Mey, Diana Lin, Christina May, Jihong Jiang, Joshua Bridgers, Brett Caswell, Kieran O’Neill, Frederick S. Vizeacoumar, Mackenzie MacAuley, Emilie Haniak, Charles Craddock, Paresh Vyas, Luca Malcovati, Rena Buckstein, Michelle Moksa, Martin Hirst, Franco J. Vizeacoumar, Nadia Medvedev, Michael Heuser, Ryan J. Stubbins, Yu Deng, Aly Karsan
Institutions: University of Saskatchewan, Saskatchewan Cancer Agency, Queen Elizabeth Hospital Birmingham, University of Birmingham, University of Oxford, MRC Weatherall Institute of Molecular Medicine, MRC Molecular Haematology Unit, University of Pavia, Policlinico San Matteo Fondazione, Sunnybrook Health Science Centre, University of British Columbia, BC Cancer Agency, Canada's Michael Smith Genome Sciences Centre, University Hospital in Halle, Martin Luther University Halle-Wittenberg, Vancouver Coastal Health
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G3165317950, G5955368233, G777032340
OpenAlex ID: W7162103728