MDM2 inhibitors in myeloid cancers: from basic biology to clinical use in myeloproliferative neoplasms.

The MDM2-p53 autoregulatory loop is a central regulator of cellular stress responses, and in myeloid neoplasms-including acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN)-p53 is frequently retained but functionally suppressed through MDM2 overexpression and oncogenic signaling, notably via JAK-STAT activation.

MDM2-p53自调节环路是细胞应激反应的主要调节器，在包括急性髓细胞性白血病（AML）和骨髓增殖性肿瘤（MPN）在内的髓系肿瘤中，p53通常被保留但通过MDM2过度表达和致癌信号通路，特别是通过JAK-STAT激活，功能上受到抑制。

Over the past decade, successive generations of MDM2 inhibitors have translated structural and mechanistic insights into clinical investigation, yielding critical lessons regarding dosing paradigms, hematologic toxicity, biomarker-driven patient selection, and mechanisms of resistance, including TP53-mutant clonal selection.

在过去十年中，连续几代MDM2抑制剂将结构和机制洞察转化为临床研究，提供了关于剂量方案、血液毒性、基于生物标志物的患者选择以及耐药机制（包括TP53突变克隆选择）的关键教训。

While early phase III trials in AML were negative, recent studies in myelofibrosis demonstrate clinically meaningful spleen, symptom, and molecular responses, supporting disease-modifying potential in TP53-wild-type settings.

虽然早期的III期试验在急性髓细胞性白血病中结果为阴性，但最近在骨髓纤维化中的研究表明，对于TP53野生型情况，脾脏、症状和分子反应具有临床意义，支持其疾病修饰潜力。

Adaptive platform designs and rational combinations with JAK inhibitors, BCL-2 antagonists, and interferons have further refined therapeutic strategies.

适应性平台设计以及与JAK抑制剂、BCL-2拮抗剂和干扰素的合理组合进一步精细化了治疗策略。

Emerging MDM2 degraders and next-generation agents aim to overcome feedback limitations and improve therapeutic index.

新兴的MDM2降解剂和新一代药物旨在克服反馈限制并提高治疗指数。

This review integrates mechanistic foundations, clinical development, resistance biology, and future directions, highlighting how decades of basic science have reshaped p53 reactivation into a precision therapeutic paradigm in myeloid disease.

这篇综述整合了机制基础、临床发展、耐药生物学和未来方向，强调了几十年的基础科学研究如何将p53再激活重塑为髓系疾病的精准治疗范式。