Isoform-Specific Roles and Therapeutic Targeting of RUNX1 in Hematopoiesis and Leukemogenesis

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Abstract
Runt-related transcription factor 1 (RUNX1) is a key transcription factor in hematopoiesis, producing multiple major isoforms, RUNX1A, B, and C, via alternative promoter usage and splicing. These isoforms have distinct roles in hematopoiesis and leukemogenesis. Imbalances in isoform expression, such as RUNX1A overexpression or RUNX1C loss, contribute to leukemogenesis in disorders. RUNX1 isoform expression is regulated by transcriptional, epigenetic, and splicing mechanisms and is further influenced by genome architecture. Pathogenic variants, including truncations and fusion proteins, disrupt isoform homeostasis and transcriptional control for the target genes in hematopoiesis. Recent therapeutic strategies aim to restore isoform balance rather than inhibit RUNX1 globally. Approaches include splice-switching oligonucleotides, CRISPR-based promoter modulation, and enhancer-targeted therapies. Understanding isoform-specific RUNX1 biology offers new opportunities for precision treatment of hematologic malignancies.
Funding Information
  • Hankuk University of Foreign Studies Research Fund (RS-2025-00556460)
  • the Gyeonggi Regional Innovation System & Education Project (Gyeonggi RISE Project) (RS-2025-00556460)
  • Ministry of Education and Gyeonggi Province (RS-2025-00556460)
  • National Research Foundation of Korea (RS-2025-00556460)
  • National Research Foundation of Korea (RS-2025-00556460)

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