Introduction:TP53is the most commonly mutated gene in human cancers and was the first tumor suppressor gene to be discovered in the history of medical science. Mutations in theTP53gene occur at various genetic locations and exhibit significant heterogeneity among patients. Mutations occurring primarily within the DNA-binding domain ofTP53result in the loss of the p53 protein’s DNA-binding capability. However, a complex phenotypic landscape often combines gain-of-function, dominant negative, or altered specificity features. This complexity poses a significant challenge in developing an effective treatment strategy, which eradicatesTP53-mutated cancer clones. This review summarizes the current understanding ofTP53mutations in AML and their implications.TP53mutation in AML: In patients with acute myeloid leukemia (AML), six hotspot mutations (R175H, G245S, R248Q/W, R249S, R273H/S, and R282W) within the DNA-binding domain are common.TP53mutations are frequently associated with a complex karyotype and subgroups of therapy-related or secondary AML. The presence ofTP53mutation is considered as a poor prognostic factor.TP53-mutated AML is even classified as a distinct subgroup of AML by itself, asTP53-mutated AML exhibits a significantly distinct landscape in terms of co-mutation and gene expression profiles compared with wildtype (WT)-TP53AML. Clinical Implications: To better predict the prognosis in cancer patients with differentTP53mutations, several predictive scoring systems have been proposed based on screening experiments, to assess the aggressiveness ofTP53-mutated cancer cells. Among those scoring systems, a relative fitness score (RFS) could be applied to AML patients withTP53mutations in terms of overall survival (OS) and event-free survival (EFS). The current standard treatment, which includes cytotoxic chemotherapy and allogeneic hematopoietic stem cell transplantation, is largely ineffective for patients withTP53-mutated AML. Consequently, most patients withTP53-mutated AML succumb to leukemia within several months, despite active anticancer treatment. Decitabine, a hypomethylating agent, is known to be relatively effective in patients with AML. Numerous trials are ongoing to investigate the effects of novel drugs combined with hypomethylating agents,TP53-targeting agents or immunologic agents. Conclusions: Developing an effective treatment strategy forTP53-mutated AML through innovative and multidisciplinary research is an urgent task. Directly targeting mutatedTP53holds promise as an approach to combatingTP53-mutated AML, and recent developments in immunologic agents for AML offer hope in this field.
引言：TP53是人类癌症中最常见的突变基因，也是医学史上首个被发现的肿瘤抑制基因。TP53基因的突变发生在不同的遗传位点，且在患者间表现出显著的异质性。主要发生在TP53 DNA结合结构域的突变会导致p53蛋白丧失DNA结合能力。然而，复杂的表型特征往往同时包含功能获得性、显性负性或特异性改变等特性。这种复杂性对制定有效清除TP53突变癌细胞克隆的治疗策略构成了重大挑战。本综述总结了目前对急性髓系白血病（AML）中TP53突变及其临床意义的认识。 AML中的TP53突变：在急性髓系白血病患者中，DNA结合结构域内存在六个常见的热点突变（R175H、G245S、R248Q/W、R249S、R273H/S和R282W）。TP53突变常与复杂核型及治疗相关或继发性AML亚群相关。TP53突变的存在被视为不良预后因素。TP53突变AML甚至被单独归类为AML的一个独特亚型，因为与野生型TP53 AML相比，TP53突变AML在共突变谱和基因表达谱方面表现出显著差异。 临床意义：为更好预测携带不同TP53突变的癌症患者预后，基于筛选实验已提出多种预测评分系统，用于评估TP53突变癌细胞的侵袭性。在这些评分系统中，相对适应性评分（RFS）可应用于TP53突变AML患者的总生存期（OS）和无事件生存期（EFS）评估。当前包含细胞毒性化疗和异基因造血干细胞移植的标准治疗方案对TP53突变AML患者疗效有限。因此，尽管接受积极抗癌治疗，大多数TP53突变AML患者仍在数月内死于白血病。去甲基化药物地西他滨已知对AML患者具有相对疗效。目前正在进行多项临床试验，研究新型药物联合去甲基化药物、TP53靶向药物或免疫制剂的效果。 结论：通过创新性多学科研究制定针对TP53突变AML的有效治疗策略是当前紧迫任务。直接靶向突变TP53有望成为对抗TP53突变AML的有效途径，而AML免疫治疗药物的最新进展为该领域带来了希望。
TP53Mutation in Acute Myeloid Leukemia: An Old Foe Revisited
肿瘤(癌症)患者之家