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<p>Despite most acute myeloid leukemia (AML) patients achieving complete remission after induction chemotherapy, two-thirds relapse within 5 years. AML follows a cellular hierarchy sustained by leukemia stem cells (LSCs), which drive tumor progression and relapse. Little is known about the genetic determinants driving LSCs stemness properties. By identifying chromatin variants from accessibility measurements across LSCs, hematopoietic stem cells and downstream progeny, we identified transposable elements (TEs) as genetic determinants of primitive versus mature populations. Accessibility at 121 TE subfamilies distinguished LSCs from mature leukemic cells and stratified AML patients by stemness and survival. Functional assays revealed that these TE subfamilies serve as docking sites for genome topology regulators or lineage-specific transcription factors, including LYL1 in LSCs. Chromatin editing established the necessity of accessibility at LTR12C elements to maintain LSC stemness. Thus, TEs regulate primitive versus mature cell states, with distinct subfamilies underlying stemness in normal versus leukemic stem cells.</p>

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Transposable elements shape stemness in normal and leukemic hematopoiesis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月4日

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  • Giacomo Grillo,
  • Bettina Nadorp,
  • Aditi Qamra,
  • Bryce Drylie,
  • Amanda Mitchell,
  • Christopher Arlidge,
  • Ankita Nand,
  • Naoya Takayama,
  • Alex Murison,
  • Seyed Ali Madani Tonekaboni,
  • Komaldeep Kaur Kang,
  • Andrea Arruda,
  • Jean C. Y. Wang,
  • Mark D. Minden,
  • Özgen Deniz,
  • Héléna Boutzen,
  • John E. Dick,
  • Mathieu Lupien

摘要

Despite most acute myeloid leukemia (AML) patients achieving complete remission after induction chemotherapy, two-thirds relapse within 5 years. AML follows a cellular hierarchy sustained by leukemia stem cells (LSCs), which drive tumor progression and relapse. Little is known about the genetic determinants driving LSCs stemness properties. By identifying chromatin variants from accessibility measurements across LSCs, hematopoietic stem cells and downstream progeny, we identified transposable elements (TEs) as genetic determinants of primitive versus mature populations. Accessibility at 121 TE subfamilies distinguished LSCs from mature leukemic cells and stratified AML patients by stemness and survival. Functional assays revealed that these TE subfamilies serve as docking sites for genome topology regulators or lineage-specific transcription factors, including LYL1 in LSCs. Chromatin editing established the necessity of accessibility at LTR12C elements to maintain LSC stemness. Thus, TEs regulate primitive versus mature cell states, with distinct subfamilies underlying stemness in normal versus leukemic stem cells.