Jepsen Vera H, Hanel Andrea, Picard Daniel, Bhave Rigveda, Hasselmann Rebecca, Mehtonen Juha, Schliehe-Diecks Julian, Kath Carla-Johanna, Suppiyar Vithusan, Prasad Yash, Schaal Katerina, Tu Jia-Wey, Rüchel Nadine, Kameri Ersen, Qin Nan, Wang Herui, Zhuang Zhengping, Wagener Rabea, Blümel Lena, Lautwein Tobias, Hein Daniel, Koppstein David, Kögler Gesine, Remke Marc, Bhatia Sanil, Heinäniemi Merja, Borkhardt Arndt, Fischer Ute
Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty Heinrich Heine University Düsseldorf Germany.
German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf Düsseldorf Germany.
Hemasphere. 2025 Apr 2;9(4):e70116. doi: 10.1002/hem3.70116. eCollection 2025 Apr.
, 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 + preleukemic cells still remain elusive. In this study, we identify linker histone H1-0 as a critical mediator of the + 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 in + hiPSCs that was preserved upon hematopoietic differentiation. Moreover, whole transcriptome data of 1,727 leukemia patient samples showed significantly elevated levels in + BCP-ALL compared to other leukemia entities. Using dual-luciferase promoter assays, we show that ETV6::RUNX1 induces promoter activity. We further demonstrate that depletion of H1-0 specifically inhibits ETV6::RUNX1 signature genes, including and . Single-cell sequencing showed that 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 + transcriptome and indicate that the addition of Quisinostat may be beneficial to target non-responsive or relapsing + BCP-ALL.
，是小儿B细胞前体急性淋巴细胞白血病（BCP-ALL）中最常见的致癌融合基因，它会引发一种临床上无症状的白血病前期状态，这种状态在携带者体内可持续十多年，并可能在获得继发性病变后发展为明显的白血病。导致ETV6::RUNX1白血病前期细胞静止的机制仍然难以捉摸。在本研究中，我们通过使用CRISPR/Cas9基因编辑技术构建的人类诱导多能干细胞（hiPSC）模型，将连接组蛋白H1-0鉴定为ETV6::RUNX1白血病前期状态的关键调节因子。全基因组表达分析显示，ETV6::RUNX1 hiPSC中H1-0上调，并且在造血分化后得以保留。此外，1727例白血病患者样本的全转录组数据显示，与其他白血病实体相比，ETV6::RUNX1+ BCP-ALL中H1-0水平显著升高。使用双荧光素酶启动子分析，我们发现ETV6::RUNX1可诱导H1-0启动子活性。我们进一步证明，H1-0的缺失特异性抑制ETV6::RUNX1特征基因，包括MEIS1和HOXA9。单细胞测序表明，H1-0在静止造血细胞中高表达。重要的是，H1-0蛋白水平与BCP-ALL细胞对组蛋白去乙酰化酶抑制剂（HDACis）的敏感性相对应，使用诱导H1-0的HDACi Quisinostat进行联合治疗与已有的化疗药物显示出有前景的协同作用。综上所述，我们的数据将H1-0鉴定为ETV6::RUNX1转录组的关键调节因子，并表明添加Quisinostat可能有利于靶向无反应或复发的ETV6::RUNX1+ BCP-ALL。
