文章：

TP53突变型骨髓增生异常综合征/急性髓系白血病的骨髓微环境病理生物学及治疗机会

Marrow Microenvironmental Pathobiology and Therapeutic Opportunities forTP53-Mutated Myelodysplastic Syndrome/Acute Myeloid Leukemia

原文发布日期：16 January 2026

DOI: 10.3390/cancers18020275

类型: Article

开放获取: 是

英文摘要：

Mutations inTP53inhibit p53 protective behaviors including cell cycle arrest, DNA damage repair protein recruitment, and apoptosis. The ubiquity of p53 in genome-stabilizing functions leads to an aberrant tumor microenvironment inTP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Profound immunosuppression mediated by myeloid-derived suppressor cells, the upregulation of cytokines and cell-surface receptors on leukemic cells, the suppression of native immune regulator cells, and metabolic aberrations in the bone marrow are features of theTP53-mutated AML/MDS marrow microenvironment. These localized changes in the bone marrow microenvironment (BMME) explain why traditional therapies for MDS/AML, including chemotherapeutics and hypomethylating agents, are not as effective inTP53-mutated myeloid neoplasms and demonstrate the dire need for new treatments in this patient population. The unique pathophysiology ofTP53-mutated disease also provides new therapeutic approaches which are being studied, including intracellular targets (MDM2, p53), cell-surface protein biologics (immune checkpoint inhibitors, BiTE therapy, and antibody–drug conjugates), cell therapies (CAR-T, NK-cell), signal transduction pathways (Hedgehog, Wnt, NF-κB, CCRL2, and HIF-1α), and co-opted biologic pathways (cholesterol synthesis and glycolysis). In this review, we will discuss the pathophysiologic anomalies of the tumor microenvironment inTP53-mutant MDS/AML, the hypothesized mechanisms of chemoresistance it imparts, and how novel therapies are leveraging diverse therapeutic targets to address this critical area of need.

摘要翻译： 

TP53基因突变会抑制p53的保护性作用，包括细胞周期停滞、DNA损伤修复蛋白募集以及细胞凋亡。p53在维持基因组稳定性方面的广泛功能缺失，导致TP53突变的骨髓增生异常综合征（MDS）和急性髓系白血病（AML）中形成异常的肿瘤微环境。其特征包括：髓系来源的抑制细胞介导的深度免疫抑制、白血病细胞上细胞因子与细胞表面受体的上调、天然免疫调节细胞的抑制，以及骨髓内的代谢异常。骨髓微环境的这些局部变化解释了为何传统MDS/AML疗法（包括化疗药物和去甲基化药物）对TP53突变的髓系肿瘤疗效有限，并凸显了该患者群体对新疗法的迫切需求。TP53突变疾病的独特病理生理机制也为新疗法提供了研究方向，包括针对细胞内靶点（MDM2、p53）、细胞表面蛋白生物制剂（免疫检查点抑制剂、双特异性T细胞衔接器治疗和抗体偶联药物）、细胞疗法（CAR-T、NK细胞）、信号转导通路（Hedgehog、Wnt、NF-κB、CCRL2和HIF-1α）以及协同生物通路（胆固醇合成和糖酵解）的治疗策略。本综述将探讨TP53突变型MDS/AML肿瘤微环境的病理生理异常、其介导化疗耐药的假设机制，以及新型疗法如何通过多靶点治疗策略应对这一关键临床需求。

原文链接：

Marrow Microenvironmental Pathobiology and Therapeutic Opportunities forTP53-Mutated Myelodysplastic Syndrome/Acute Myeloid Leukemia