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<p>Acute erythroleukemia (AEL) is a rare and highly aggressive subtype of acute myeloid leukemia (AML) that is often accompanied by splenomegaly in some patients. Using the Friend murine leukemia virus clone 57 (F-MuLV clone 57) mouse model, we observed lactate accumulation in the spleens of mice with late-stage disease. Proteomic profiling indicated dysregulation of the glycolysis/gluconeogenesis pathway and aberrant activity of its key enzymes. In vitro, lactate alone directly induced macrophage polarization to the pro-inflammatory M1 phenotype. This lactate-rich milieu reprograms macrophage function, favoring M1 polarization. A self-reinforcing cycle thus emerges in the AEL splenic microenvironment: lactate drives M1 polarization, and these M1 macrophages subsequently elevate their glycolytic activity, amplifying local lactate production that further promotes M1 polarization. In vivo, pharmacological inhibition of lactate production with Oxamate disrupted this cycle, reversed pathogenic M1 polarization, ameliorated splenomegaly, and extended survival. These results identify lactate as a key immunomodulatory factor in the splenic microenvironment that accelerates AEL progression. Targeting this lactate-driven metabolic-immune axis represents a novel adjunctive strategy for mitigating splenomegaly and disease progression in AEL.</p><p></p>

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Lactate-mediated macrophage polarization promotes splenomegaly in acute erythroleukemia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月25日

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  • Mingyue Yang,
  • Dan Xie,
  • Yanlong Zhang,
  • Yi Ye,
  • Suwen Yang,
  • Hongqian Zhu,
  • Sha Cheng,
  • Jia Yu,
  • Ningning Zan,
  • Shengwen Huang,
  • Heng Luo

摘要

Acute erythroleukemia (AEL) is a rare and highly aggressive subtype of acute myeloid leukemia (AML) that is often accompanied by splenomegaly in some patients. Using the Friend murine leukemia virus clone 57 (F-MuLV clone 57) mouse model, we observed lactate accumulation in the spleens of mice with late-stage disease. Proteomic profiling indicated dysregulation of the glycolysis/gluconeogenesis pathway and aberrant activity of its key enzymes. In vitro, lactate alone directly induced macrophage polarization to the pro-inflammatory M1 phenotype. This lactate-rich milieu reprograms macrophage function, favoring M1 polarization. A self-reinforcing cycle thus emerges in the AEL splenic microenvironment: lactate drives M1 polarization, and these M1 macrophages subsequently elevate their glycolytic activity, amplifying local lactate production that further promotes M1 polarization. In vivo, pharmacological inhibition of lactate production with Oxamate disrupted this cycle, reversed pathogenic M1 polarization, ameliorated splenomegaly, and extended survival. These results identify lactate as a key immunomodulatory factor in the splenic microenvironment that accelerates AEL progression. Targeting this lactate-driven metabolic-immune axis represents a novel adjunctive strategy for mitigating splenomegaly and disease progression in AEL.