Oncogenic Modulation of MAPK Signaling in Leukemia via SPNS2-Mediated Sphingosine Metabolism Rewiring

Lipid metabolism rewiring is an essential determinant of cancer transformation and progression, yet metabolic checkpoints that act as key switches in this process remain poorly defined. Using functional genomics in a mouse model of acute myeloid leukemia (AML), we identified the sphingosine-1-phosphate transporter SPNS2 as a sphingolipid checkpoint protein critical for leukemia development. SPNS2 expression is regulated by MYC and progressively decreases with AML differentiation, highlighting its tumor-suppressive role in a subset of Core Binding Factor AMLs. Integrating lipidomic profiling, RNA-seq, flow cytometry, and microscopy with gain- and loss-of-function approaches, we showed that SPNS2 modulation rewires sphingolipid metabolism by altering sphingomyelin levels, thereby affecting membrane nanodomain formation, active RAS localization and MAPK signaling. Exogenous reintroduction of SPNS2 decreases sphingomyelin levels, disrupts nanodomain organization, and limits leukemic progression in AML mouse models. Our data revealed an unrecognized mechanism by which sphingolipid transport dynamics intersect with oncogenic signaling to control cancer progression.