The protein deacetylase HDAC10 controls DNA replication in malignant lymphoid cells

IF 12.8 1区医学 Q1 HEMATOLOGY

Leukemia Pub Date : 2025-04-29 DOI:10.1038/s41375-025-02612-8

Andreas O. Mieland, Giuseppe Petrosino, Mario Dejung, Jia-Xuan Chen, Amitkumar Fulzele, Fereshteh Mahmoudi, Jia-Wey Tu, Al-Hassan M. Mustafa, Yanira Zeyn, Christoph Hieber, Matthias Bros, Tina M. Schnöder, Florian H. Heidel, Sara Najafi, Ina Oehme, Ilse Hofmann, Mike Schutkowski, Sebastian Hilscher, Christian Kosan, Falk Butter, Sanil Bhatia, Wolfgang Sippl, Oliver H. Krämer

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Abstract

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.

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蛋白去乙酰化酶HDAC10控制恶性淋巴样细胞的DNA复制

组蛋白去乙酰化酶（hdac）包括一个由18个表观遗传修饰因子组成的家族。HDAC10在白血病细胞中的生物学相关功能尚不清楚。我们证明了人类培养的急性B细胞/T细胞白血病和淋巴瘤细胞需要HDAC10的催化活性才能存活。在这些细胞中，HDAC10控制myc依赖的DNA聚合酶亚基POLD1的转录诱导。因此，药物抑制HDAC10会导致DNA断裂和聚adp核糖链的积累。这些过程最终导致caspase依赖性细胞凋亡。PZ48不损害静息和增殖的人类正常血细胞。PZ48对ALL细胞的体内活性在小鼠小鼠模型中得到验证。这些数据揭示了HDAC10的核功能。HDAC10控制MYC-POLD1轴以维持DNA复制的进程和基因组的完整性。这种机制定义的“hdac10”可以作为淋巴细胞恶性肿瘤的治疗选择。

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来源期刊

Leukemia 医学-血液学

CiteScore

18.10

自引率

3.50%

发文量

270

审稿时长

3-6 weeks

期刊介绍： Title: Leukemia Journal Overview: Publishes high-quality, peer-reviewed research Covers all aspects of research and treatment of leukemia and allied diseases Includes studies of normal hemopoiesis due to comparative relevance Topics of Interest: Oncogenes Growth factors Stem cells Leukemia genomics Cell cycle Signal transduction Molecular targets for therapy And more Content Types: Original research articles Reviews Letters Correspondence Comments elaborating on significant advances and covering topical issues