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

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.