Oncogenic modulation of MAPK signaling in leukemia via SPNS2-driven sphingolipid metabolism and membrane nanodomains remodeling

Lipid metabolism rewiring is an essential determinant of cancer progression, yet the key metabolic checkpoints which govern this process remain poorly defined. Using functional genomics in a mouse model of acute myeloid leukemia (AML), we identify the sphingosine-1-phosphate transporter SPNS2 as a critical sphingolipid checkpoint protein which modulates leukemia progression. SPNS2 expression is regulated by MYC and progressively declines during AML differentiation, highlighting its tumor-suppressive role in a subset of Core Binding Factor AMLs. By integrating steady-state and serine isotope-tracing lipidomics, RNA sequencing, flow cytometry, and high-resolution microscopy, with gain- and loss-of-function approaches, we show that SPNS2 modulation rewires sphingolipid metabolism by modifying sphingomyelin abundance. This remodeling alters membrane nanodomain organization, active RAS localization, and MAPK signaling. Exogenous reintroduction of SPNS2 decreases sphingomyelin levels, disrupts nanodomain organization, and limits leukemic progression in various AML mouse models. We further reveal in a cohort of patients with AML that low SPNS2 expression is associated with increased sensitivity to MAPK pathway inhibition, and demonstrate functionally in vivo that SPNS2 silencing sensitizes AML cells to MEK1/2 inhibition. Collectively, our data reveal a mechanism by which sphingolipid transport dynamics intersect with oncogenic signaling to control cancer progression.