Histone Lactylation‐Mediated <scp>RANKL</scp> Activation in Early T‐Cell Precursor Acute Lymphoblastic Leukemia Impairs Neural Stem Cell Self‐Renewal During <scp>CNS</scp> Infiltration

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a recently recognized high-risk T lymphoblastic leukemia (T-ALL) subgroup, which is an immunophenotypic subtype with a high risk of infiltrating the central nervous system (CNS), leading to CNS leukemia and associated neurological and psychiatric symptoms. Prior studies have identified molecular mechanisms and pathways mediating ETP-ALL cell entry into the CNS. Nevertheless, CNS-directed therapy is associated with long-term adverse effects, encompassing neurocognitive impairments and secondary malignancies. Therefore, identification of the mechanisms underlying the effects of ETP-ALL infiltration on neurogenesis within the CNS is urgently needed. In this study, we observed elevated lactate levels and widespread lactate modification sites in ETP-ALL cells, especially with H3K18la levels significantly upregulated compared to non-ETP-ALL cells. We found that H3K18la levels in ETP-ALL impair human neural stem cells (hNSCs) self-renewal by suppressing proliferation and disrupting their differentiation capacity. Furthermore, we discovered that H3K18la inhibits neurogenesis through transcriptional activation of receptor activator of nuclear factor-kappa b ligand (RANKL). This research contributes to a deeper understanding of the mechanism of ETP-ALL's impact on neurogenesis of the CNS, potentially paving the way for novel therapeutic strategies targeting CNS ETP-ALL leukemia.