目前临床发现急性髓系白血病（AML）患者往往伴随铁过载现象，且铁过载引发一系列并发症甚至影响患者寿命。祛铁治疗能够明显缓解症状，但其影响白血病发生发展的作用机制迄今未明。我们前期发现铁过载与白血病炎症之间密切相关，白血病相关巨噬细胞（LAM）铁过载，且表型趋于炎性极化。结合前期研究和文献报道，我们推测：白血病铁过载调控LAM铁代谢异常及炎性极化，形成慢性炎症微环境，促进白血病发生发展。在预实验的基础上，本项目拟AML（MLL-AF9）铁过载小鼠为模型，探讨铁过载调控LAM极化和功能的作用机制，并鉴定铁诱导LAM炎性极化的分子靶点。同时联合筛选临床常用铁螯合剂和信号通路抑制剂，对关键通路的分子进行干预，验证其逆转或改善LAM铁代谢及极化，延长白血病生存期的作用效果和机制。本项目将丰富机体铁代谢调控免疫炎性反应相关理论，为铁螯合疗法和巨噬细胞靶向治疗白血病提供新的思路和方法。

Iron overload is frequently observed in patients with acute myeloid leukemia (AML), leading to significantly serious complications and even affecting both quality of life and overall survival. Patients showed an improvement in symptoms after the initiation of iron chelation therapy. However, mechanisms of iron overload on the initiation and progression of leukemia remain elusive. In pre-experiments, we found that iron overload was intimately related to leukemic inflammatory responses, furthermore, leukemia associated macrophage (LAM) with high iron level had more M1 inflammatory characteristics. Combined with the previous work and references, we hypothesize that: Iron overload in leukemia modulates iron metabolism of LAM, which dictates LAM polarization and function, influencing the formation of chronic inflammation microenvironment, and promote the leukemia progression. Based on the results of pre-experiments, next, the study will be conducted to investigate the systematic role of iron overload in LAM polarization and function by using iron-overload AML mouse model. We will not only look for potential molecular target for iron-mediated LAM polarization, but also identity the efficiency of iron chelating agents used in clinical, on rescuing the iron metabolism and polarization of LAM, and prolonging the survival of leukemia. The knowledge gained by this study will improve the overall understanding of how iron metabolism modulates leukemic inflammatory response, furthermore, the study provides novel clues for the combination of iron chelation therapy and macrophage-based therapeutic application against leukemia.