Transposable elements shape stemness in normal and leukemic hematopoiesis.

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.