Initial leukemic epigenomic state determines hypomethylating agent response
Published in Nature Communications, 2026
Recommended citation: Gopal, A., Tam, D., Mey, F., Lin, D., May, C., Jiang, J., Bridgers, J., Caswell, B., O'Neill, K., Vizeacoumar, F.S., MacAuley, M., Haniak, E., Craddock, C., Vyas, P., Malcovati, L., Buckstein, R., Moksa, M., Vizeacoumar, F.J., Medvedev, N., Heuser, M., Stubbins, R.J., Deng, Y. & Karsan, A. (2026). "Initial leukemic epigenomic state determines hypomethylating agent response." Nature Communications https://doi.org/10.1038/s41467-026-73334-3
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.