急性髓系白血病(AML),造血干细胞的侵袭性恶性肿瘤,以细胞分化阻断为特征,不受控制的扩散,和细胞扩增会损害健康的造血功能,并导致全血细胞减少和感染易感性。几种遗传和染色体畸变在AML中起作用并影响患者预后。TP53是参与多种细胞特征的关键抑癌基因,如细胞周期调节,基因组稳定性,扩散,分化,干细胞稳态,凋亡,新陈代谢,衰老,以及响应细胞应激的DNA损伤修复。在AML中,TP53改变发生在5%-12%的新生AML病例中。这些突变形成了一个重要的分子亚群,在AML患者中,具有这些突变的患者预后最差,总生存期最短,即使接受了积极的化疗和同种异体干细胞移植。TP53突变频率在复发性和复发性AML中增加,并与化疗耐药相关。AML遗传学和生物学的进展带来了新疗法,然而,对于TP53突变导致疾病的患者,这些药物的临床获益在很大程度上仍未被探索.本文综述了TP53突变疾病的分子特征;TP53对白血病的某些标志的影响。特别是代谢重组和免疫逃避,TP53突变的临床重要性;以及治疗TP53突变疾病的临床前和临床治疗策略的当前进展。
Acute myeloid leukemia (AML), an aggressive malignancy of hematopoietic stem cells, is characterized by the blockade of cell differentiation, uncontrolled proliferation, and cell expansion that impairs healthy hematopoiesis and results in pancytopenia and susceptibility to infections. Several genetic and chromosomal aberrations play a role in AML and influence patient outcomes. TP53 is a key tumor suppressor gene involved in a variety of cell features, such as cell-cycle regulation, genome stability, proliferation, differentiation, stem-cell homeostasis, apoptosis, metabolism, senescence, and the repair of DNA damage in response to cellular stress. In AML, TP53 alterations occur in 5%-12% of de novo AML cases. These mutations form an important molecular subgroup, and patients with these mutations have the worst prognosis and shortest overall survival among patients with AML, even when treated with aggressive chemotherapy and allogeneic stem cell transplant. The frequency of TP53-mutations increases in relapsed and recurrent AML and is associated with chemoresistance. Progress in AML genetics and biology has brought the novel therapies, however, the clinical benefit of these agents for patients whose disease is driven by TP53 mutations remains largely unexplored. This review focuses on the molecular characteristics of TP53-mutated disease; the impact of TP53 on selected hallmarks of leukemia, particularly metabolic rewiring and immune evasion, the clinical importance of TP53 mutations; and the current progress in the development of preclinical and clinical therapeutic strategies to treat TP53-mutated disease.