A PTBP1–CDC42 splicing axis regulates leukemia growth and venetoclax sensitivity in acute myeloid leukemia
Abstract
Acute myeloid leukemia (AML) is an aggressive blood cancer characterized by high rates of relapse and poor outcomes, especially in elderly or unfit patients, who cannot tolerate intensive chemotherapy. While the BCL2 inhibitor venetoclax has improved initial responses in this high-risk population, relapses remain nearly universal, highlighting the need for novel therapeutic strategies. Here, we identify the RNA-binding protein PTBP1 as a critical dependency in AML. PTBP1 depletion impairs leukemic growth in vitro and in vivo , and is associated with widespread splicing alterations and global disruption of protein synthesis. Integrative transcriptomic and iCLIP analyses reveal that PTBP1 orchestrates a splicing program centered on Rho GTPase signaling, with CDC42 as a key downstream effector. Mechanistically, PTBP1 loss triggers a splicing switch from CDC42-v1 to CDC42-v2, leading to reduced GTPase activity and impaired protein synthesis. Pharmacological inhibition of CDC42 selectively induces cytotoxicity in AML cells, while sparing healthy hematopoietic cells. Importantly, CDC42 inhibition markedly enhances venetoclax anti-leukemic efficacy. These findings establish PTBP1 as a critical regulator of AML cell fitness and identify a clinically actionable therapeutic combination that exploits AML dependency on PTBP1-CDC42 signaling to enhance the efficacy of venetoclax-based regimens.
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BibTeX
@misc{oberling2026ptbp1cdc42,
title = {{A PTBP1–CDC42 splicing axis regulates leukemia growth and venetoclax sensitivity in acute myeloid leukemia}},
author = {Margaux Oberling and Mathieu Landry and Yann Aubert and Manon Faivre and Alexandre Gay and Alexandre Boudet and Anaïs Granjon and Ambrine Sahal and Sarah Bertoli and François Vergez and Véronique Mansat-de Mas and Christian Récher and Clément Larrue and Laura Poillet and Jean-Emmanuel Sarry and Carine Joffre and Manuel D Diaz-Munoz and Vera Pancaldi and Margherita Ghisi},
howpublished = {HAL},
year = {2026},
month = aug,
doi = {10.64898/2026.08.25.745954},
url = {https://hal.science/hal-05862176v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - UNPB
TI - A PTBP1–CDC42 splicing axis regulates leukemia growth and venetoclax sensitivity in acute myeloid leukemia
AU - Margaux Oberling
AU - Mathieu Landry
AU - Yann Aubert
AU - Manon Faivre
AU - Alexandre Gay
AU - Alexandre Boudet
AU - Anaïs Granjon
AU - Ambrine Sahal
AU - Sarah Bertoli
AU - François Vergez
AU - Véronique Mansat-de Mas
AU - Christian Récher
AU - Clément Larrue
AU - Laura Poillet
AU - Jean-Emmanuel Sarry
AU - Carine Joffre
AU - Manuel D Diaz-Munoz
AU - Vera Pancaldi
AU - Margherita Ghisi
PY - 2026
DA - 2026/08/26
PB - HAL
DO - 10.64898/2026.08.25.745954
UR - https://hal.science/hal-05862176v1
AB - Acute myeloid leukemia (AML) is an aggressive blood cancer characterized by high rates of relapse and poor outcomes, especially in elderly or unfit patients, who cannot tolerate intensive chemotherapy. While the BCL2 inhibitor venetoclax has improved initial responses in this high-risk population, relapses remain nearly universal, highlighting the need for novel therapeutic strategies. Here, we identify the RNA-binding protein PTBP1 as a critical dependency in AML. PTBP1 depletion impairs leukemic growth in vitro and in vivo , and is associated with widespread splicing alterations and global disruption of protein synthesis. Integrative transcriptomic and iCLIP analyses reveal that PTBP1 orchestrates a splicing program centered on Rho GTPase signaling, with CDC42 as a key downstream effector. Mechanistically, PTBP1 loss triggers a splicing switch from CDC42-v1 to CDC42-v2, leading to reduced GTPase activity and impaired protein synthesis. Pharmacological inhibition of CDC42 selectively induces cytotoxicity in AML cells, while sparing healthy hematopoietic cells. Importantly, CDC42 inhibition markedly enhances venetoclax anti-leukemic efficacy. These findings establish PTBP1 as a critical regulator of AML cell fitness and identify a clinically actionable therapeutic combination that exploits AML dependency on PTBP1-CDC42 signaling to enhance the efficacy of venetoclax-based regimens.
ER -