Transposable elements in hematopoietic stem cells upon aging and myeloid malignancies.

Abstract

Transposable elements (TEs) constitute nearly half of the human genome and profoundly influence hematopoietic stem cell (HSC) biology. In this review, we synthesize current evidence demonstrating that TEs exert dual and context-dependent roles in HSCs during steady-state hematopoiesis, stress responses, aging, and leukemogenesis. Under basal conditions, tightly controlled TE activity can be beneficial for HSC biology, through the induction of intrinsic type I interferon signaling and a fine-tuned control of gene expression. However, dysregulated TE activation upon stresses and aging can undermine HSC self-renewal, impair genomic integrity, and drive age-associated hematopoietic decline. TEs also play a dual role in leukemogenesis. Derepression of transcription factor motifs within TEs can activate oncogenic programs, while TE-derived nucleic acids can simultaneously elicit antiviral and DNA damage responses that trigger anti-tumoral p53- or interferon-dependent growth arrest or apoptosis. The balance between these pro- and anti-tumoral effects remains an open question, likely shaped by cellular context, TE subtypes, and the magnitude of TE expression. Finally, we discuss the potential to therapeutically modulate TE activity. Understanding TE dynamics in HSCs offers new opportunities for mechanistic insight and clinical innovation in myeloid malignancies.