HIF-1α和 EZH2 在急性髓系白血病中的作用机制及临床意义

Mechanisms and clinical significance of HIF-1α and EZH2 in acute myeloid leukemia

摘要

急性髓系白血病（acute myeloid leukemia，AML）是一种高度异质性和侵袭性的造血系统恶性肿瘤，其发生发展受多种分子机制影响，涉及遗传突变、信号通路异常、表观遗传调控及肿瘤微环境相互作用等多个层面。缺氧诱导因子-1α（hypoxia inducible factor-1α，HIF-1α）是细胞应答低氧环境的关键调控因子，其异常高表达与AML不良预后相关联；Zeste增强子同源物2（enhancer of zeste homolog 2，EZH2）作为成人AML中国诊疗指南中认定的高危基因之一，既可因基因突变丧失其抑癌作用，也可在特定阶段通过过表达维持白血病干细胞特性并介导化疗耐药，表现出时空动态的双重调控功能。研究表明，HIF-1α和EZH2在AML中可能通过代谢-表观遗传互作轴实现协同调控，共同促进白血病细胞的增殖、分化受阻以及免疫逃避。文章全面回顾HIF-1α和EZH2在AML中的表达特点、生物学功能、相互作用机制以及临床转化潜能，希望给AML的发生发展机制研究以及联合靶向干预策略提供理论支撑和研究方向。

Abstract

Acute myeloid leukemia（AML）is a highly heterogeneous and aggressive hematologic malignancy whose pathogenesis and progression are influenced by a variety of molecular mechanisms. These encompass genetic mutations，aberrant signaling pathways，epigenetic dysregulation，and complex interactions within the tumor microenvironment. Hypoxia-inducible factor-1α（HIF-1α），a master regulator of cellular response to low oxygen tension，is frequently overexpressed in AML，and its abnormal expression is closely associated with poor patient prognosis. The histone methyltransferase enhancer of zeste homolog 2（EZH2），recognized as a high-risk molecular marker in the Chinese adult AML diagnosis and treatment guidelines，exhibits a context-dependent dual regulatory role. It can lose its tumor-suppressive function through loss-of-function mutations，while in specific disease stages，its overexpression contributes to maintaining leukemia stem cell properties and mediating chemotherapy resistance. Research indicates that HIF-1α and EZH2 may engage in synergistic crosstalk in AML，potentially forming a“metabolism-epigenetics”axis. This interaction creates a positive feedback loop that cooperatively promotes leukemia cell proliferation， blocks differentiation，facilitates metabolic reprogramming，and aids in immune evasion. This article provides a comprehensive review of the expression patterns，biological functions，interaction mechanisms，and clinical translational potential of HIF-1α and EZH2 in AML. The aim is to offer a theoretical foundation and suggest research directions for a deeper understanding of AML pathogenesis and the development of novel combination targeted therapy strategies.

关键词

急性髓系白血病 / 缺氧诱导因子-1α / Zeste增强子同源物2 / 预后标志物 / 靶向治疗

Key words

acute myeloid leukemia / hypoxia-inducible factor-1α / enhancer of zeste homolog 2 / prognostic biomarker / targeted therapy

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基金资助

国家自然科学基金(82500240)