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<p>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 <i>HOXB4</i>, 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.</p>

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Initial leukemic epigenomic state determines hypomethylating agent response

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月22日

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  • 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

摘要

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.