Stabilization of the PP2A-B56α complex overcomes venetoclax-azacitidine resistance by impairing OXPHOS in AML
13 affiliations
- 1Clinical Neuroproteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), UPNA, Navarra, Spain.
- 2Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain.
- 3Centro de Investigación Médica Aplicada and
- 4Department of Biochemistry and Genetics, University of Navarra, Pamplona, Spain.
- 5Department of Internal Medicine, Division of Genetic Medicine, The University of Michigan Medical School, Ann Arbor, Michigan, USA.
- 6Roger Cancer Center, The University of Michigan Health, Ann Arbor, Michigan, USA.
- 7Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain.
- 8Instituto Murciano de Investigación Biosanitaria (IMIB) Pascual Parrilla, Murcia, Spain.
- 9Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
- 10Department of Pharmacology, Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
- 11Hematology Service, HUN, Pamplona, Spain.
- 12Cancer and Aging Group, Hospital Universitario Virgen de la Arrixaca, and IMIB, Murcia, Spain.
- 13Department of Cancer Biology, The University of Michigan, Ann Arbor, Michigan, USA.
Abstract
Cell metabolic rewiring is associated with resistance to venetoclax-azacitidine (Ven-Aza) combination therapy and relapse in patients with acute myeloid leukemia (AML). Drug-resistant cells exhibit an enhanced reliance on oxidative phosphorylation (OXPHOS) for energy production. Therefore, impairing mitochondrial metabolism represents an exciting strategy to face this unmet clinical need. We recently demonstrated that the specific activation of the phosphatase PP2A-B56α enhances the proapoptotic efficacy of venetoclax in AML. Here, through leveraging unbiased multi-omics–based approaches and using both genetic and pharmacological tools, we define key roles for the tumor suppressor PP2A-B56α complex in OXPHOS regulation and treatment response in disease-relevant AML models. From a translational perspective, the specific stabilization of PP2A-B56α heterocomplex with the potentially novel PP2A molecular glue activator, RPT04402, reduces OXPHOS levels in treatment-resistant AML cells and improves treatment response in both Ven-Aza–sensitive and –resistant AML cell lines, primary cells, and in vivo models. Together, our work supports further research on targeted combination therapy approaches based on PP2A-B56α stabilization to counteract OXPHOS-related treatment resistance and improve AML responses in a patient population with historically poor outcomes.
Related
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BibTeX
@article{romeromurillo2026stabilization,
title = {{Stabilization of the PP2A-B56α complex overcomes venetoclax-azacitidine resistance by impairing OXPHOS in AML}},
author = {Silvia Romero-Murillo and Irene Peris and Anna Maria Lucianò and Nerea Marcotegui and Carmen Vicente and Brian Tran and Kelsey Barrie and Caitlin M. O’Connor and Andrea Torres-López and Maria C. Mateos and Maria L. Cayuela and Victoriano Mulero and Joaquín Fernández-Irigoyen and Enrique Santamaría and Maria D. Odero and Goutham Narla},
journal = {JCI Insight},
year = {2026},
month = sep,
doi = {10.1172/jci.insight.205218},
url = {https://doi.org/10.1172/jci.insight.205218},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Stabilization of the PP2A-B56α complex overcomes venetoclax-azacitidine resistance by impairing OXPHOS in AML
AU - Silvia Romero-Murillo
AU - Irene Peris
AU - Anna Maria Lucianò
AU - Nerea Marcotegui
AU - Carmen Vicente
AU - Brian Tran
AU - Kelsey Barrie
AU - Caitlin M. O’Connor
AU - Andrea Torres-López
AU - Maria C. Mateos
AU - Maria L. Cayuela
AU - Victoriano Mulero
AU - Joaquín Fernández-Irigoyen
AU - Enrique Santamaría
AU - Maria D. Odero
AU - Goutham Narla
PY - 2026
DA - 2026/09/15
JO - JCI Insight
DO - 10.1172/jci.insight.205218
UR - https://doi.org/10.1172/jci.insight.205218
AB - Cell metabolic rewiring is associated with resistance to venetoclax-azacitidine (Ven-Aza) combination therapy and relapse in patients with acute myeloid leukemia (AML). Drug-resistant cells exhibit an enhanced reliance on oxidative phosphorylation (OXPHOS) for energy production. Therefore, impairing mitochondrial metabolism represents an exciting strategy to face this unmet clinical need. We recently demonstrated that the specific activation of the phosphatase PP2A-B56α enhances the proapoptotic efficacy of venetoclax in AML. Here, through leveraging unbiased multi-omics–based approaches and using both genetic and pharmacological tools, we define key roles for the tumor suppressor PP2A-B56α complex in OXPHOS regulation and treatment response in disease-relevant AML models. From a translational perspective, the specific stabilization of PP2A-B56α heterocomplex with the potentially novel PP2A molecular glue activator, RPT04402, reduces OXPHOS levels in treatment-resistant AML cells and improves treatment response in both Ven-Aza–sensitive and –resistant AML cell lines, primary cells, and in vivo models. Together, our work supports further research on targeted combination therapy approaches based on PP2A-B56α stabilization to counteract OXPHOS-related treatment resistance and improve AML responses in a patient population with historically poor outcomes.
SN - 2379-3708
ER -