ADH5/ALDH2脱氢酶和DNA聚合酶θ保护正常和恶性造血细胞免受甲醛攻击：治疗意义

ADH5/ALDH2 dehydrogenases and DNA polymerase theta protect normal and malignant hematopoietic cells from formaldehyde challenge: therapeutic implications.

作者信息

Atkins Jessica, Kukuyan Anna-Mariya, Toma Monika, Drzewiecka Malgorzata, Vekariya Umeshkumar, Karami Adam, Nieborowska-Skorska Margaret, Nejati Reza, Hadzijusufovic Emir, Valent Peter, Stoklosa Tomasz, Sliwinski Tomasz, Wasik Mariusz, Skorski Tomasz

机构信息

Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.

Department of Molecular Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland.

出版信息

Leukemia. 2025 Jul 10. doi: 10.1038/s41375-025-02687-3.

DOI:10.1038/s41375-025-02687-3

PMID:40640557

Abstract

Normal hematopoietic stem and progenitor cells (HSPCs) are exposed to physiological levels of formaldehyde but occasionally may be challenged by high levels of formaldehyde generated by endogenous and exogenous sources. In addition, leukemia cells stressed by oncogenic mutations continuously produce excessive amounts of formaldehyde. Here, we show that DNA polymerase theta (Polθ) cooperates with alcohol dehydrogenase 5 (ADH5) and aldehyde dehydrogenase 2 (ALDH2) to protect healthy and malignant HSPCs challenged by formaldehyde. ADH5 and ALDH2 metabolize formaldehyde while Polθ-mediated DNA repair by microhomology-dependent end-joining (TMEJ) protects cells from the lethal effect of DNA double strand breaks resulting from formaldehyde-mediated DNA-protein crosslinks. Genetic or pharmacological targeting of ADH5 or ALDH2 enhanced the effect of Polθ inhibitors in leukemic cells. Thus, ADH5/ALDH2 cooperate with Polθ to protect normal HSPCs sporadically challenged by high levels of formaldehyde, and inhibition of Polθ and ADH5 or ALDH2 may exert an anti-leukemic effect.

摘要

正常造血干细胞和祖细胞（HSPCs）会接触到生理水平的甲醛，但偶尔可能会受到内源性和外源性来源产生的高水平甲醛的挑战。此外，受到致癌突变应激的白血病细胞会持续产生过量的甲醛。在此，我们表明DNA聚合酶θ（Polθ）与乙醇脱氢酶5（ADH5）和乙醛脱氢酶2（ALDH2）协同作用，以保护受到甲醛挑战的健康和恶性HSPCs。ADH5和ALDH2代谢甲醛，而Polθ通过微同源性依赖的末端连接（TMEJ）介导的DNA修复保护细胞免受甲醛介导的DNA-蛋白质交联导致的DNA双链断裂的致死效应。对ADH5或ALDH2进行基因或药物靶向可增强Polθ抑制剂在白血病细胞中的作用。因此，ADH5/ALDH2与Polθ协同作用，保护偶尔受到高水平甲醛挑战的正常HSPCs，抑制Polθ以及ADH5或ALDH2可能会发挥抗白血病作用。