TCF3::HLF orchestrates an enhancer-promoter network with activation of MEF2C to promote immature HSC gene expression in leukemia.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 42090509.
- Also identified by DOI 10.1126/sciadv.adu3728 and PMC identifier 13148343.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Oncogenic fusion transcription factors (TFs) frequently drive hematopoietic malignancies by altering gene expression in key developmental programs. TCF3::HLF is a fusion TF that characterizes a rare, treatment-resistant subtype of B cell acute lymphoblastic leukemia [t(17;19) TCF3::HLF-positive B-ALL]. Despite its clinical significance, the mechanisms by which TCF3::HLF induces leukemia are unclear. We used HiChIP mapping and genetic interference to analyze TCF3::HLF at the 3D genome level, revealing enhancer-promoter interactions that control gene activation or repression. Notably, TCF3::HLF directly regulates <i>MEF2C</i> expression through its enhancer, as interference disrupted <i>MEF2C</i> transcription and inhibited leukemia propagation. This disruption also diminished embryonal hematopoietic stem cell (HSC) gene signatures and restored mature HSC and B-lymphoid markers. These findings highlight <i>MEF2C</i> as a critical component of the transcriptional network reprogrammed by TCF3::HLF. Our study provides insight into how TCF3::HLF rewires the 3D genome to drive leukemia and serves as a resource for further exploration of the TCF3::HLF regulome.
Medical subject headings
- Promoter Regions, Genetic
- Hematopoietic Stem Cells
- Gene Expression Regulation, Leukemic
- MEF2 Transcription Factors
- Enhancer Elements, Genetic
- Leukemia
- Gene Regulatory Networks
- Transcription Factor 7-Like 2 Protein