Department of Hematology and Oncology, University of Texas Health Science-Houston, Houston, TX 77030, USA.
Department of Leukemia, The University of Texas-MD Anderson Cancer Center-Houston, Houston, TX 77030, USA.
Int J Mol Sci. 2021 Oct 5;22(19):10782. doi: 10.3390/ijms221910782.
Mutation of the tumor suppressor gene, , is associated with abysmal survival outcomes in acute myeloid leukemia (AML). Although it is the most commonly mutated gene in cancer, its occurrence is observed in only 5-10% of de novo AML, and in 30% of therapy related AML (t-AML). mutation serves as a prognostic marker of poor response to standard-of-care chemotherapy, particularly in t-AML and AML with complex cytogenetics. In light of a poor response to traditional chemotherapy and only a modest improvement in outcome with hypomethylation-based interventions, allogenic stem cell transplant is routinely recommended in these cases, albeit with a response that is often short lived. Despite being frequently mutated across the cancer spectrum, progress and enthusiasm for the development of p53 targeted therapeutic interventions is lacking and to date there is no approved drug that mitigates the effects of mutation. There is a mounting body of evidence indicating that p53 mutants differ in functionality and form from typical AML cases and subsequently display inconsistent responses to therapy at the cellular level. Understanding this pathobiological activity is imperative to the development of effective therapeutic strategies. This review aims to provide a comprehensive understanding of the effects of on the hematopoietic system, to describe its varying degree of functionality in tumor suppression, and to illustrate the need for the adoption of personalized therapeutic strategies to target distinct classes of the p53 mutation in AML management.
肿瘤抑制基因 的突变与急性髓系白血病（AML）的极差生存结局相关。尽管它是癌症中最常发生突变的基因，但在新发 AML 中仅观察到 5-10%，在治疗相关 AML（t-AML）中观察到 30%。 突变是对标准治疗化疗反应不良的预后标志物，特别是在 t-AML 和具有复杂细胞遗传学的 AML 中。鉴于对传统化疗的反应不佳，并且基于低甲基化的干预措施仅略微改善了结果，在这些情况下通常建议进行同种异体干细胞移植，尽管反应通常是短暂的。尽管在癌症谱中经常发生突变，但针对 p53 靶向治疗干预的进展和热情仍然缺乏，迄今为止，没有批准的药物可以减轻 突变的影响。越来越多的证据表明，p53 突变体在功能和形式上与典型的 AML 病例不同，随后在细胞水平上对治疗的反应不一致。了解这种病理生物学活性对于制定有效的治疗策略至关重要。本综述旨在全面了解 对造血系统的影响，描述其在肿瘤抑制中的不同功能程度，并说明需要采用个性化的治疗策略来靶向 AML 管理中不同类别的 p53 突变。
