TY  - JOUR
AU  - Jepsen, Vera H
AU  - Hanel, Andrea
AU  - Picard, Daniel Joseph
AU  - Bhave, Rigveda
AU  - Hasselmann, Rebecca
AU  - Mehtonen, Juha
AU  - Schliehe-Diecks, Julian
AU  - Kath, Carla-Johanna
AU  - Suppiyar, Vithusan
AU  - Prasad, Yash
AU  - Schaal, Katerina
AU  - Tu, Jia-Wey
AU  - Rüchel, Nadine
AU  - Kameri, Ersen
AU  - Qin, Nan
AU  - Wang, Herui
AU  - Zhuang, Zhengping
AU  - Wagener, Rabea
AU  - Blümel, Lena
AU  - Lautwein, Tobias
AU  - Hein, Daniel
AU  - Koppstein, David
AU  - Kögler, Gesine
AU  - Remke, Marc
AU  - Bhatia, Sanil
AU  - Heinäniemi, Merja
AU  - Borkhardt, Arndt
AU  - Fischer, Ute
TI  - H1-0 is a specific mediator of the repressive ETV6::RUNX1 transcriptional landscape in preleukemia and B cell acute lymphoblastic leukemia.
JO  - HemaSphere
VL  - 9
IS  - 4
SN  - 2572-9241
CY  - Hoboken
PB  - John Wiley & Sons Ltd.
M1  - DKFZ-2025-00730
SP  - e70116
PY  - 2025
AB  - ETV6::RUNX1, the most common oncogenic fusion in pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL), induces a clinically silent preleukemic state that can persist in carriers for over a decade and may progress to overt leukemia upon acquisition of secondary lesions. The mechanisms contributing to quiescence of ETV6::RUNX1+ preleukemic cells still remain elusive. In this study, we identify linker histone H1-0 as a critical mediator of the ETV6::RUNX1+ preleukemic state by employing human -induced pluripotent stem cell (hiPSC) models engineered by using CRISPR/Cas9 gene editing. Global gene expression analysis revealed upregulation of H1-0 in ETV6::RUNX1+ hiPSCs that was preserved upon hematopoietic differentiation. Moreover, whole transcriptome data of 1,727 leukemia patient samples showed significantly elevated H1-0 levels in ETV6::RUNX1+ BCP-ALL compared to other leukemia entities. Using dual-luciferase promoter assays, we show that ETV6::RUNX1 induces H1-0 promoter activity. We further demonstrate that depletion of H1-0 specifically inhibits ETV6::RUNX1 signature genes, including RAG1 and EPOR. Single-cell sequencing showed that H1-0 is highly expressed in quiescent hematopoietic cells. Importantly, H1-0 protein levels correspond to susceptibility of BCP-ALL cells towards histone deacetylase inhibitors (HDACis) and combinatorial treatment using the H1-0-inducing HDACi Quisinostat showed promising synergism with established chemotherapeutic drugs. Taken together, our data identify H1-0 as a key regulator of the ETV6::RUNX1+ transcriptome and indicate that the addition of Quisinostat may be beneficial to target non-responsive or relapsing ETV6::RUNX1+ BCP-ALL.
LB  - PUB:(DE-HGF)16
C6  - pmid:40177616
C2  - pmc:PMC11962653
DO  - DOI:10.1002/hem3.70116
UR  - https://inrepo02.dkfz.de/record/300277
ER  -