Oncogenic modulation of MAPK signaling in leukemia via SPNS2-driven sphingolipid metabolism and membrane nanodomains remodeling
Abstract
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.
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BibTeX
@article{sodaro2026oncogenic,
title = {{Oncogenic modulation of MAPK signaling in leukemia via SPNS2-driven sphingolipid metabolism and membrane nanodomains remodeling}},
author = {Gaetano Sodaro and Khansa Saadallah and Swann Bredin and Michel Kahi and Frank Ling and Paul-Arthur Meslin and Hélène Pasquer and Christopher F. Bassil and Jonathan Paz Montoya and Jean Andrea Maillat and Julie Lesieur and Chloé Zédouard and Nario Tomishige and Nina Fenouille and Matthieu Duchmann and Raphaël Itzykson and Arnaud Jacquel and Patrick Auberger and Kris C. Wood and Toshihide Kobayashi and Camille Lobry and Giovanni D’Angelo and Lina Benajiba and Alexandre Puissant},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78821-1},
url = {https://www.nature.com/articles/s41467-026-78821-1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Oncogenic modulation of MAPK signaling in leukemia via SPNS2-driven sphingolipid metabolism and membrane nanodomains remodeling
AU - Gaetano Sodaro
AU - Khansa Saadallah
AU - Swann Bredin
AU - Michel Kahi
AU - Frank Ling
AU - Paul-Arthur Meslin
AU - Hélène Pasquer
AU - Christopher F. Bassil
AU - Jonathan Paz Montoya
AU - Jean Andrea Maillat
AU - Julie Lesieur
AU - Chloé Zédouard
AU - Nario Tomishige
AU - Nina Fenouille
AU - Matthieu Duchmann
AU - Raphaël Itzykson
AU - Arnaud Jacquel
AU - Patrick Auberger
AU - Kris C. Wood
AU - Toshihide Kobayashi
AU - Camille Lobry
AU - Giovanni D’Angelo
AU - Lina Benajiba
AU - Alexandre Puissant
PY - 2026
DA - 2026/10/28
JO - Nature Communications
DO - 10.1038/s41467-026-78821-1
UR - https://www.nature.com/articles/s41467-026-78821-1
AB - 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.
SN - 2041-1723
ER -