Central nervous system (CNS) relapse of B-cell acute lymphoblastic leukemia (B-ALL), the most common childhood cancer, is associated with a dismal prognosis of 35% 5-year survival rate, and no new drugs have been licensed for CNS leukemia since the 1960s. Cytology of the cerebrospinal fluid (CSF) is the conventional method for diagnosis of CNS involvement of leukemia but is limited by low sensitivity when compared to post-mortem autopsy analysis of leukemic involvement (44%). As such, CNS leukemia often likely exists below the threshold of cytologic detection at diagnosis, with nearly 60% of CNS relapses occurring in patients initially cytologically negative. Given this finding, we performed single-cell sequencing of diagnostic CSF and paired bone marrow samples from pediatric leukemia patients with known CNS involvement. Interestingly, we found that leukemia cells in the CSF exhibit distinct transcriptomic signatures compared to their counterparts in the bone marrow. In particular, leukemic populations exhibited enrichment of genes associated with biological processes such as metabolism, inflammatory response, and mTOR signaling, suggesting that leukemia cells may undergo CNS-niche specific adaptations upon migration from the bone marrow to the CNS. Furthermore, we found that leukemia cells exhibit differential engraftment in the CNS, such as higher infiltration in ventricular and/or leptomeningeal structures compared to parenchymal regions using in vivo and in vitro models of CNS leukemia. Taken together, our findings suggest that distinct microenvironmental cues in the brain may contribute to CNS leukemic cell adaptations that support their survival and persistence, which may lay the foundation for facilitating development of targeted therapeutic strategies for CNS leukemia.

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2025
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