MYB activity drives emergent enhancer activation and enhancer-promoter interactions in acute lymphoblastic leukemia

Journal article

Aberrant enhancer usage is a defining feature of oncogenic transcriptional reprogramming. Therapeutic strategies that disrupt enhancer-driven gene regulation may offer new treatment avenues. MYB is a key hematopoietic transcription factor that is frequently dysregulated in a broad range of cancers and plays a critical role in sustaining malignant cell states, including in aggressive leukemia subtypes such as KMT2A-rearranged (KMT2A-r) leukemias. The molecular mechanisms by which it maintains oncogenic transcription remain incompletely understood. Here, we investigate the role of MYB in directing pathological enhancer activity to drive oncogene expression in leukemia. Using high-resolution Micro-Capture-C, we show that upon MYB degradation, highly defined enhancer-promoter interactions at MYB binding sites are lost, correlating with significant downregulation of target gene expression. When anchored to a gene desert region, the Myb transactivation domain (MybTA) is sufficient and necessary for nucleation of an enhancer-like region. Critically, long-range chromatin interactions are established up to 400 kb away from where MybTA is anchored. This results in the activation of transcription from distal cryptic elements, which is reduced or abolished in the presence of point mutations that disrupt its interaction with the co-activators P300/CBP. Together, these results indicate that MYB activity alone is sufficient to generate an enhancer, inducing transcription through precise enhancer-promoter crosstalk, and identify the MYB-P300/CBP axis as a therapeutically actionable vulnerability in enhancer-driven malignancies.

Authors: Lau, I-J; Bloye, G; Smith, AL; Harman, JR; Hamley, JC

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Society of Hematology (ASH Publications)
• Journal: Blood
• Place of publication: United States
• Publication date: 2026-03-19
• Acceptance date: 2026-02-21
• DOI: 10.1182/blood.2025030424
• EISSN: 1528-0020
• ISSN: 0006-4971
• Pmid: 41949410
• Language: English
• Keywords: hematology; childhood leukemia; pediatric research initiative; rare diseases; cancer genomics; pediatric cancer; genetics; human genome; cancer