# Lactate-mediated macrophage polarization promotes splenomegaly in acute erythroleukemia

## TL;DR

This study shows that lactate in the spleen promotes aggressive leukemia by changing immune cells, and blocking lactate can reduce disease severity.

## Contribution

The novel contribution is identifying lactate as a driver of macrophage polarization and disease progression in acute erythroleukemia.

## Key findings

- Lactate accumulation in the spleen reprograms macrophages to a pro-inflammatory M1 phenotype.
- Pharmacological inhibition of lactate production reduces splenomegaly and improves survival in a mouse model of AEL.
- A self-reinforcing cycle of lactate-driven M1 polarization accelerates AEL progression.

## Abstract

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.