Gopal A., Tam D., Mey F., Lin D., May C., Jiang J., Bridgers J., Caswell B., O'Neill K., Vizeacoumar FS., MacAuley M., Haniak E., Craddock C., Vyas P., Malcovati L., Buckstein R., Moksa M., Hirst M., Vizeacoumar FJ., Medvedev N., Heuser M., Stubbins RJ., Deng Y., Karsan A.

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.

Initial leukemic epigenomic state determines hypomethylating agent response.

Gopal A., Tam D., Mey F., Lin D., May C., Jiang J., Bridgers J., Caswell B., O'Neill K., Vizeacoumar FS., MacAuley M., Haniak E., Craddock C., Vyas P., Malcovati L., Buckstein R., Moksa M., Hirst M., Vizeacoumar FJ., Medvedev N., Heuser M., Stubbins RJ., Deng Y., Karsan A.

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