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

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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.

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