Glycolysis Induces Abnormal Transcription Through Histone Lactylation in T-lineage Acute Lymphoblastic Leukemia.

The Warburg effect, which excessively produce lactate, and transcriptional dysregulation are two hallmarks of tumors. However, the precise influence of lactate on epigenetic modifications at a genome-wide level and its impact on gene transcription in tumor cells remain unclear. We conducted an analysis of genome-wide histone H3 lysine 18 lactylation (H3K18la) modifications in T-cell acute lymphoblastic leukemia (T-ALL). We found an increased level of lactate and H3K18la in T-ALL tumor cells compared to normal T cells and the H3K18la modification is associated with cell proliferation. Accordingly, we observed a significant shift in genome-wide H3K18la modification from T cell immunity in normal T cells to leukemogenesis in T-ALL, which correlated with altered gene transcription profiles. We showed that H3K18la is primarily involved in actively regulating gene transcription and observed clusters of H3K18la modifications exhibiting patterns reminiscent of super-enhancers. Disrupting H3K18la modification revealed both synergistic and divergent changes between H3K18la and histone H3 lysine 27 acetylation (H3K27ac) modifications. Finally, we found that the high transcription of H3K18la target genes, IGFBP2 and IARS, is associated with inferior prognosis of T-ALL. These findings enhance our understanding of how metabolic disruptions contribute to transcription dysregulation through epigenetic changes in T-ALL, underscoring the interplay of histone modifications in maintaining oncogenic epigenetic stability.