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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Journal
Nature Communications
Published
2026-10-28
DOI
https://doi.org/10.1038/s41467-026-78821-1
Primary Topic
Sphingolipid Metabolism and Signaling
Type
article
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article

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

Raphaël Itzykson, Paul-Arthur Meslin, Gaetano Sodaro, Camille Lobry et al.
Nature Communications
Sphingolipid Metabolism and Signaling
article

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

Raphaël Itzykson, Paul-Arthur Meslin, Gaetano Sodaro, Camille Lobry, Michel Kahi, Frank Ling, Arnaud Jacquel, Hélène Pasquer, Julie Lesieur, Alexandre Puissant, Patrick Auberger, Matthieu Duchmann, Lina Benajiba, Jonathan Paz Montoya, Giovanni D’Angelo, Kris Cameron Wood, Khansa Saadallah, Nario Tomishige, Christopher F. Bassil, Nina Fenouille, Swann Bredin, Toshihide Kobayashi, Jean Andrea Maillat, Chloé Zédouard
article en

Abstract

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.

Nature Communications
Centre National de la Recherche Scientifique (FR), Inserm (FR), Duke University (US), Université Paris Cité (FR), Sorbonne Paris Cité (FR), Assistance Publique – Hôpitaux de Paris (FR), Centre Méditerranéen de Médecine Moléculaire (FR), Institut Cochin (FR), Hôpital Saint-Louis (FR), Laboratoire Image, Ville, Environnement (FR), Centre d'Investigation Clinique Saint-Louis (FR), École Polytechnique Fédérale de Lausanne (CH), Université de Strasbourg (FR)
Amgen, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, École Supérieure de Physique et de Chimie Industrielles de la Ville de Paris, Fondation ARC pour la Recherche sur le Cancer, Fondation de France, Institut National Du Cancer, Direction Générale de l’offre de Soins, National Institutes of Health
Good health and well-being
Openalex Percentile: Top 23%
Sphingolipid Metabolism and Signaling
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