蛋白质脱乙酰酶HDAC10控制恶性淋巴细胞中的DNA复制。
The protein deacetylase HDAC10 controls DNA replication in malignant lymphoid cells.
作者信息
Mieland Andreas O, Petrosino Giuseppe, Dejung Mario, Chen Jia-Xuan, Fulzele Amitkumar, Mahmoudi Fereshteh, Tu Jia-Wey, Mustafa Al-Hassan M, Zeyn Yanira, Hieber Christoph, Bros Matthias, Schnöder Tina M, Heidel Florian H, Najafi Sara, Oehme Ina, Hofmann Ilse, Schutkowski Mike, Hilscher Sebastian, Kosan Christian, Butter Falk, Bhatia Sanil, Sippl Wolfgang, Krämer Oliver H
机构信息
Institute of Toxicology, Mainz University Medical Center, Mainz, Germany.
Institute of Molecular Biology (IMB), Core Facility Bioinformatics, Mainz, Germany.
出版信息
Leukemia. 2025 Apr 29. doi: 10.1038/s41375-025-02612-8.
Histone deacetylases (HDACs) comprise a family of 18 epigenetic modifiers. The biologically relevant functions of HDAC10 in leukemia cells are enigmatic. We demonstrate that human cultured and primary acute B cell/T cell leukemia and lymphoma cells require the catalytic activity of HDAC10 for their survival. In such cells, HDAC10 controls a MYC-dependent transcriptional induction of the DNA polymerase subunit POLD1. Consequently, pharmacological inhibition of HDAC10 causes DNA breaks and an accumulation of poly-ADP-ribose chains. These processes culminate in caspase-dependent apoptosis. PZ48 does not damage resting and proliferating human normal blood cells. The in vivo activity of PZ48 against ALL cells is verified in a Danio rerio model. These data reveal a nuclear function for HDAC10. HDAC10 controls the MYC-POLD1 axis to maintain the processivity of DNA replication and genome integrity. This mechanistically defined "HDAC10ness" may be exploited as treatment option for lymphoid malignancies.
组蛋白去乙酰化酶（HDACs）由18种表观遗传修饰因子组成。HDAC10在白血病细胞中的生物学相关功能尚不明确。我们证明，人类培养的原代急性B细胞/T细胞白血病和淋巴瘤细胞的存活需要HDAC10的催化活性。在这类细胞中，HDAC10控制着DNA聚合酶亚基POLD1的MYC依赖性转录诱导。因此，HDAC10的药理学抑制会导致DNA断裂和聚ADP-核糖链的积累。这些过程最终导致半胱天冬酶依赖性凋亡。PZ48不会损害静息和增殖的人类正常血细胞。PZ48对急性淋巴细胞白血病（ALL）细胞的体内活性在斑马鱼模型中得到验证。这些数据揭示了HDAC10的核功能。HDAC10控制MYC-POLD1轴以维持DNA复制的持续性和基因组完整性。这种从机制上定义的“HDAC10特性”可作为淋巴恶性肿瘤的治疗选择加以利用。
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