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Clinical challenges in the diagnosis and treatment of ALL in the CNS arise from an incomplete understanding of CNS disease pathogenesis, a significant barrier to developing novel therapeutics and biomarkers to address these challenges. A concerted research effort over recent years has significantly improved our understanding of CNS disease pathogenesis in ALL. Numerous CNS-infiltrating mechanisms by ALL cells have been uncovered, so recent research focuses on how ALL persists in this site. The role of the CNS microenvironment in the survival and therapy resistance of ALL is emerging, driven by ALL cell adhesion and metabolic reprogramming, revealing pathways with therapeutic potential. Here, we integrate recent advances in CNS infiltration and persistence in ALL, focusing on the signaling and metabolic frameworks that enable leukemic survival and therapy resistance once established in this site. We also evaluate novel therapeutic avenues and emerging targeted therapies that could enhance the efficacy of CNS-directed therapy in ALL.<\/jats:p>","DOI":"10.1038\/s41375-026-03060-8","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T12:15:50Z","timestamp":1784290550000},"page":"1854-1867","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Central nervous system involvement in acute lymphoblastic leukemia: pathogenesis and targeted therapy"],"prefix":"10.1038","volume":"40","author":[{"given":"Luke","family":"Quinlan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Yeung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7497-6477","authenticated-orcid":false,"given":"Susan","family":"Heatley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4844-333X","authenticated-orcid":false,"given":"Deborah","family":"White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8990-2574","authenticated-orcid":false,"given":"Elyse","family":"Page","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"3060_CR1","doi-asserted-by":"publisher","first-page":"2382","DOI":"10.1038\/s41375-024-02395-4","volume":"38","author":"SR Rheingold","year":"2024","unstructured":"Rheingold SR, Bhojwani D, Ji L, Xu X, Devidas M, Kairalla JA, et al. 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