H1-0 is a specific mediator of the repressive ETV6::RUNX1 transcriptional landscape in preleukemia and B cell acute lymphoblastic leukemia

Vera H Jepsen; Andrea Hanel; Daniel Picard; Rigveda Bhave; Rebecca Hasselmann; Juha Mehtonen; Julian Schliehe-Diecks; Carla-Johanna Kath; Vithusan Suppiyar; Yash Prasad; Katerina Schaal; Jia-Wey Tu; Nadine Rüchel; Ersen Kameri; Nan Qin; Herui Wang; Zhengping Zhuang; Rabea Wagener; Lena Blümel; Tobias Lautwein; Daniel Hein; David Koppstein; Gesine Kögler; Marc Remke; Sanil Bhatia; Merja Heinäniemi; Arndt Borkhardt; Ute Fischer

doi:10.1002/hem3.70116

H1-0 is a specific mediator of the repressive ETV6::RUNX1 transcriptional landscape in preleukemia and B cell acute lymphoblastic leukemia

Hemasphere. 2025 Apr 2;9(4):e70116. doi: 10.1002/hem3.70116. eCollection 2025 Apr.

Authors

Vera H Jepsen^{1

2

3}, Andrea Hanel⁴, Daniel Picard^{1

2

3

5}, Rigveda Bhave^{1

3

6}, Rebecca Hasselmann^{1

2

3}, Juha Mehtonen⁴, Julian Schliehe-Diecks^{1

2

3}, Carla-Johanna Kath^{1

3

6}, Vithusan Suppiyar^{2

7}, Yash Prasad^{1

2

3}, Katerina Schaal^{1

2

3}, Jia-Wey Tu^{1

2

3}, Nadine Rüchel^{1

2

3}, Ersen Kameri^{1

2

3}, Nan Qin^{1

2

3

5

8}, Herui Wang⁹, Zhengping Zhuang⁹, Rabea Wagener^{1

2

3}, Lena Blümel^{1

2

3}, Tobias Lautwein¹⁰, Daniel Hein^{1

2

3}, David Koppstein^{2

7}, Gesine Kögler^{3

6}, Marc Remke^{1

2

3

5}, Sanil Bhatia^{1

2

3}, Merja Heinäniemi⁴, Arndt Borkhardt^{1

2

3}, Ute Fischer^{1

2

3}

Affiliations

¹ Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty Heinrich Heine University Düsseldorf Germany.
² German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf Düsseldorf Germany.
³ Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD) Bonn Germany.
⁴ Institute of Biomedicine, School of Medicine University of Eastern Finland Kuopio Finland.
⁵ Medical Faculty, Institute of Neuropathology Heinrich Heine University Düsseldorf Germany.
⁶ Medical Faculty, Institute for Transplantation Diagnostics and Cell Therapeutics Heinrich Heine University Düsseldorf Germany.
⁷ German Cancer Research Center (DKFZ) Heidelberg Germany.
⁸ Spatial and Functional Screening Core facility (SFS-CF), Medical Faculty Heinrich Heine University Düsseldorf Germany.
⁹ Neuro-Oncology Branch, Center for Cancer Research National Cancer Institute, NIH Bethesda Maryland USA.
¹⁰ Genomics Transcriptomics Laboratory, Biomedical Research Center Heinrich Heine University Düsseldorf Germany.

Abstract

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.