|
| Status |
Public on Apr 09, 2025 |
| Title |
Linker histone H1-0 is a specific mediator of the ETV6::RUNX1 transcriptional landscape in preleukemia and B cell acute lymphoblastic leukemia |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
The chimeric hematopoietic transcription factor ETV6::RUNX1 is the most common oncogenic fusion in pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL). It induces a clinically silent preleukemic state that requires secondary mutations for progression to full-blown leukemia. ETV6::RUNX1 functions primarily through repression of RUNX1 binding sites. In order to elucidate the characteristic quiescent state of ETV6::RUNX1 expressing cells, we generated preleukemic human induced pluripotent stem cell (hiPSC) models from two healthy donors using CRISPR/Cas9 gene editing. We identified upregulation of linker histone H1-0 in preleukemic hiPSCs, which was preserved upon hematopoietic differentiation and transformation to overt BCP-ALL. ETV6::RUNX1 induces activity of the H1-0 promoter whereas depletion of H1-0 specifically inhibited ETV6::RUNX1 signature genes, indicating its role as a novel key mediator of the quiescent ETV6::RUNX1 transcriptional profile. Single-cell gene expression analysis revealed that H1-0 levels strongly anti-correlate with cellular transcriptional activity, resulting in particularly high expression in quiescent cells during hematopoietic development. Pharmacologically, H1-0 protein levels correspond to susceptibility of BCP-ALL towards histone deacetylase inhibitor (HDACi) treatment and our data indicate efficacy of combinatorial drug treatment using the potent H1-0-inducing HDACi Quisinostat in BCP-ALL expressing high basal H1-0 levels.
|
| |
|
| Overall design |
To analyze transcriptional changes induced by HDACi treatment, BCP-ALL cell lines were treated with 1 µM Quisinostat or DMSO for 24 hours.
|
| |
|
| Contributor(s) |
Vera Helena J, Ute F |
| Citation(s) |
- Jepsen VH, Hanel A, Picard D, Bhave R et al. H1-0 is a specific mediator of the repressive ETV6::RUNX1 transcriptional landscape in preleukemia and B cell acute lymphoblastic leukemia. Hemasphere 2025 Apr;9(4):e70116. PMID: 40177616
|
| |
| Submission date |
Nov 29, 2024 |
| Last update date |
Apr 09, 2025 |
| Contact name |
Vera Helena Jepsen |
| E-mail(s) |
VeraHelena.Jepsen@med.uni-duesseldorf.de
|
| Organization name |
University Hospital Düsseldorf
|
| Street address |
Moorenstraße 5
|
| City |
Düsseldorf |
| ZIP/Postal code |
40225 |
| Country |
Germany |
| |
|
| Platforms (1) |
| GPL34281 |
Illumina NovaSeq X (Homo sapiens) |
|
