The DNA damage response (DDR) encompasses the detection and repair of DNA lesions and is fundamental to the maintenance of genome integrity. Germ line DDR alterations underlie hereditary chromosome instability syndromes by promoting the acquisition of pathogenic structural variants in hematopoietic cells, resulting in increased predisposition to hematologic malignancies. Also frequent in hematologic malignancies are somatic mutations of DDR genes, typically arising from replication stress triggered by oncogene activation or deregulated tumor proliferation that provides a selective pressure for DDR loss. These defects impair homology–directed DNA repair or replication stress response, leading to an excessive reliance on error-prone DNA repair mechanisms that results in genomic instability and tumor progression. In hematologic malignancies, loss-of-function DDR alterations confer clonal growth advantage and adverse prognostic impact but may also provide therapeutic opportunities. Selective targeting of functional dependencies arising from these defects could achieve synthetic lethality, a therapeutic concept exemplified by inhibition of poly-(adenosine 5′-diphosphate ribose) polymerase or the ataxia telangiectasia and Rad 3 related-CHK1-WEE1 axis in malignancies harboring the BRCAness phenotype or genetic defects that increase replication stress. Furthermore, the role of DDR defects as a source of tumor immunogenicity, as well as their impact on the cross talk between DDR, inflammation, and tumor immunity are increasingly recognized, thus providing rationale for combining DDR modulation with immune modulation. The nature of the DDR–immune interface and the cellular vulnerabilities conferred by DDR defects may nonetheless be disease-specific and remain incompletely understood in many hematologic malignancies. Their comprehensive elucidation will be critical for optimizing therapeutic strategies to target DDR defects in these diseases.

中文翻译：

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血液系统恶性肿瘤中的 DNA 损伤反应缺陷：机制见解和治疗策略

DNA 损伤反应 (DDR) 包括 DNA 损伤的检测和修复，对于维持基因组完整性至关重要。种系 DDR 改变通过促进造血细胞中致病性结构变异的获得而成为遗传性染色体不稳定综合征的基础，从而导致血液恶性肿瘤的易感性增加。血液系统恶性肿瘤中也常见的是 DDR 基因的体细胞突变，通常是由癌基因激活或肿瘤增殖失调引发的复制应激引起的，为 DDR 损失提供了选择性压力。这些缺陷会损害同源导向的 DNA 修复或复制应激反应，导致过度依赖容易出错的 DNA 修复机制，从而导致基因组不稳定和肿瘤进展。在血液系统恶性肿瘤中，功能丧失的 DDR 改变赋予克隆生长优势和不良预后影响，但也可能提供治疗机会。选择性靶向这些缺陷引起的功能依赖性可以实现合成致死性，这是一种治疗概念，通过抑制含有 BRCA 的恶性肿瘤中的聚（腺苷 5'-二磷酸核糖）聚合酶或共济失调性毛细血管扩张和 Rad 3 相关的 CHK1-WEE1 轴来例证。增加复制压力的表型或遗传缺陷。此外，人们越来越认识到DDR缺陷作为肿瘤免疫原性来源的作用，及其对DDR、炎症和肿瘤免疫之间相互作用的影响，从而为将DDR调节与免疫调节相结合提供了理论基础。尽管如此，DDR 免疫界面的性质和 DDR 缺陷带来的细胞脆弱性可能具有疾病特异性，并且在许多血液恶性肿瘤中仍未完全了解。他们的全面阐明对于优化针对这些疾病中 DDR 缺陷的治疗策略至关重要。