Abstract Leukemia is the leading cause of death in cancer patients under 20 years and acute lymphoblastic leukemia (ALL) is the most diagnosed type. T-cell ALL (T-ALL) blasts frequently infiltrate the central nervous system (CNS), which serves as a sanctuary site and drives relapse. Despite standardized CNS-directed therapy in T-ALL treatment protocols ( (Thastrup et al. , Leukemia; 2022), unsuccessful clearance of blasts in the CNS niche results in little to no survival probability (Bharuca et al. , Hematology; 2020). Moreover, CNS-directed therapies cause severe neurotoxicity, especially during brain development. Therefore, we aimed to uncover T-ALL adaptation mechanisms specific to the CNS niche and assess therapies that exploit these vulnerabilities. Murine xenotransplantation studies revealed cholesterol-oriented transcriptional signatures in CNS-resident T-ALL blasts compared to those in the bone marrow. Of note, our recent work shows that cholesterol biosynthesis is tightly regulated by RNA m6A methylation in T-ALL. Cholesterol biosynthesis transcripts are hypermethylated alongside elevated transcript and protein levels. Pharmacological and transcriptional perturbation of the m6A landscape by impairing the demethylase FTO, confirmed the m6A-mediated regulation of cholesterol homeostasis (De Kesel et al. , Blood; 2025). To evaluate the therapeutic exploitability of this m6A-cholesterol axis on CNS leukemia, we utilized delipidated serum (DL) that is deprived of lipids and cholesterol, reflecting the reduced lipid and cholesterol availability in cerebrospinal fluid compared to blood plasma. This CNS-mimicking condition further increased apoptotic responses and sensitivity of T-ALL cells to FTO inhibition with bisantrene (BIS; Su et al. , Cancer Cell; 2020) or the experimental compound ZLD115 (Tarullo et al. , ACS Pharmacol. Transl. Sci. , 2024), despite an already strong dependency on FTO in standard conditions. Even under hypoxia (1% O2), a characteristic of the CNS, increased sensitivity to FTO inhibition was observed. We also revealed that T-ALL cell proliferation is more profoundly affected upon FTO silencing in a CNS-like condition. To maximally exploit the uncovered leukemic dependency on cholesterol, we then combined FTO inhibitors and cholesterol biosynthesis inhibitors, statins. This combination therapy was increasingly affecting T-ALL blast viability in DL medium compared to standard FBS-containing medium. Ongoing studies involve in vivo treatment with bisantrene, either with or without statins, to assess its effect on CNS leukemic burden and survival in xenotransplanted mice. In conclusion, our study illustrates that modulating RNA methylation, especially in combination with statins, is a promising approach to eradicate CNS-resident blasts by exploiting their dependency on cholesterol-related metabolic adaptation. Citation Format: Freya De Muyer, Jonas De Kesel, Igor Fijalkowski, Manou Wittouck, Jolien Van Laere, Nitesh D. Sharma, Ksenia Matlawska-Wasowska, Chris Halsey, Panagiotis Ntziachristos. Therapeutic exploitability of the m6a methylation-cholesterol axis to target central nervous system-residing leukemic blasts abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (6Suppl): Abstract nr A022.
Muyer et al. (Mon,) studied this question.