ABSTRACT 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.
Li et al. (Thu,) studied this question.