Linker histone H1-0 is a specific mediator of the repressive ETV6::RUNX1 transcriptional landscape

Jepsen, V. H.; Hanel, A.; Picard, D.; Mehtonen, J.; Hasselmann, R.; Schliehe-Diecks, J.; Tu, J.-W.; Bhave, R.; Kameri, E.; Qin, N.; Wang, H.; Zhuang, Z.; Wagener, R.; Blümel, L.; Lautwein, T.; Hein, D.; Kögler, G.; Remke, M.; Bhatia, S.; Heinäniemi, M.; Borkhardt, A.; Fischer, U.; Scharov, K.

doi:10.1101/2024.06.28.601221

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bioRxiv · 10.1101/2024.06.28.601221

Linker histone H1-0 is a specific mediator of the repressive ETV6::RUNX1 transcriptional landscape

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Abstract

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 leukemia. However, the molecular mechanisms contributing to the characteristic quiescence of ETV6::RUNX1+ preleukemic cells remain elusive. Here, we detect factors involved in the preleukemic state by generating human induced pluripotent stem cell (hiPSC) models using CRISPR/Cas9 gene editing. We identified upregulation of linker histone H1-0 in our preleukemic models, which was preserved upon hematopoietic differentiation and transformation to BCP-ALL. ETV6::RUNX1 induces H1-0 promoter activity whereas depletion of H1-0 specifically inhibited ETV6::RUNX1 signature genes, indicating its role as a key mediator of the ETV6::RUNX1 transcriptome. Single-cell gene expression analysis revealed high H1-0 levels in quiescent cells during hematopoiesis and inverse correlation with transcriptional activity. Pharmacologically, H1-0 protein levels correspond to susceptibility of BCP-ALL towards histone deacetylase inhibitors (HDACi). Altogether, our study provides novel insights into ETV6::RUNX1-induced quiescence and suggests that further investigation into combinatorial treatment of BCP-ALL using the H1-0- inducing HDACi Quisinostat may be worthwhile.

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Jepsen, V. H., Hanel, A., Picard, D., Mehtonen, J., Hasselmann, R., Schliehe-Diecks, J., Tu, J.-W., Bhave, R., Kameri, E., Qin, N., Wang, H., Zhuang, Z., Wagener, R., Blümel, L., Lautwein, T., Hein, D., Kögler, G., Remke, M., Bhatia, S., Heinäniemi, M., Borkhardt, A., Fischer, U., Scharov, K.. 2024-07-03. Linker histone H1-0 is a specific mediator of the repressive ETV6::RUNX1 transcriptional landscape. https://doi.org/10.1101/2024.06.28.601221

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