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ResearchIn-Press PreviewCell biologyHematology Open Access | 10.1172/jci.insight.205218

Stabilization of the PP2A-B56α complex overcomes venetoclax-azacitidine resistance by impairing OXPHOS in AML

Silvia Romero-Murillo,1 Irene Peris,2 Anna Maria Lucianò,3 Nerea Marcotegui,4 Carmen Vicente,4 Brian Tran,5 Kelsey Barrie,2 Caitlin M. O'Connor,2 Andrea Torres-López,6 Maria C. Mateos,7 Maria L. Cayuela,8 Victoriano Mulero,3 Joaquín Fernández-Irigoyen,1 Enrique Santamaría,1 Maria D. Odero,7 and Goutham Narla2

1Clinical Neuroproteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), UPNA, Pamplona, Spain

2Department of Internal Medicine: Division of Genetic Medicine, The University of Michigan Medical School, Ann Arbor, United States of America

3Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain

4Centro de Investigación Médica Aplicada, University of Navarra, Pamplona, Spain

5Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

6Hematology Service, Hospital Universitario de Navarra, Pamplona, Spain

7Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain

8Cancer and Aging Group, Hospital Universitario Virgen de la Arrixaca, and Instituto Murciano de Investigación Biosanitaria, Murcia, Spain

Find articles by Romero-Murillo, S. in: PubMed | Google Scholar

1Clinical Neuroproteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), UPNA, Pamplona, Spain

2Department of Internal Medicine: Division of Genetic Medicine, The University of Michigan Medical School, Ann Arbor, United States of America

3Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain

4Centro de Investigación Médica Aplicada, University of Navarra, Pamplona, Spain

5Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

6Hematology Service, Hospital Universitario de Navarra, Pamplona, Spain

7Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain

8Cancer and Aging Group, Hospital Universitario Virgen de la Arrixaca, and Instituto Murciano de Investigación Biosanitaria, Murcia, Spain

Find articles by Peris, I. in: PubMed | Google Scholar

1Clinical Neuroproteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), UPNA, Pamplona, Spain

2Department of Internal Medicine: Division of Genetic Medicine, The University of Michigan Medical School, Ann Arbor, United States of America

3Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain

4Centro de Investigación Médica Aplicada, University of Navarra, Pamplona, Spain

5Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

6Hematology Service, Hospital Universitario de Navarra, Pamplona, Spain

7Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain

8Cancer and Aging Group, Hospital Universitario Virgen de la Arrixaca, and Instituto Murciano de Investigación Biosanitaria, Murcia, Spain

Find articles by Lucianò, A. in: PubMed | Google Scholar

1Clinical Neuroproteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), UPNA, Pamplona, Spain

2Department of Internal Medicine: Division of Genetic Medicine, The University of Michigan Medical School, Ann Arbor, United States of America

3Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain

4Centro de Investigación Médica Aplicada, University of Navarra, Pamplona, Spain

5Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

6Hematology Service, Hospital Universitario de Navarra, Pamplona, Spain

7Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain

8Cancer and Aging Group, Hospital Universitario Virgen de la Arrixaca, and Instituto Murciano de Investigación Biosanitaria, Murcia, Spain

Find articles by Marcotegui, N. in: PubMed | Google Scholar

1Clinical Neuroproteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), UPNA, Pamplona, Spain

2Department of Internal Medicine: Division of Genetic Medicine, The University of Michigan Medical School, Ann Arbor, United States of America

3Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain

4Centro de Investigación Médica Aplicada, University of Navarra, Pamplona, Spain

5Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

6Hematology Service, Hospital Universitario de Navarra, Pamplona, Spain

7Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain

8Cancer and Aging Group, Hospital Universitario Virgen de la Arrixaca, and Instituto Murciano de Investigación Biosanitaria, Murcia, Spain

Find articles by Vicente, C. in: PubMed | Google Scholar

1Clinical Neuroproteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), UPNA, Pamplona, Spain

2Department of Internal Medicine: Division of Genetic Medicine, The University of Michigan Medical School, Ann Arbor, United States of America

3Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain

4Centro de Investigación Médica Aplicada, University of Navarra, Pamplona, Spain

5Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

6Hematology Service, Hospital Universitario de Navarra, Pamplona, Spain

7Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain

8Cancer and Aging Group, Hospital Universitario Virgen de la Arrixaca, and Instituto Murciano de Investigación Biosanitaria, Murcia, Spain

Find articles by Tran, B. in: PubMed | Google Scholar |

1Clinical Neuroproteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), UPNA, Pamplona, Spain

2Department of Internal Medicine: Division of Genetic Medicine, The University of Michigan Medical School, Ann Arbor, United States of America

3Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain

4Centro de Investigación Médica Aplicada, University of Navarra, Pamplona, Spain

5Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

6Hematology Service, Hospital Universitario de Navarra, Pamplona, Spain

7Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain

8Cancer and Aging Group, Hospital Universitario Virgen de la Arrixaca, and Instituto Murciano de Investigación Biosanitaria, Murcia, Spain

Find articles by Barrie, K. in: PubMed | Google Scholar

1Clinical Neuroproteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), UPNA, Pamplona, Spain

2Department of Internal Medicine: Division of Genetic Medicine, The University of Michigan Medical School, Ann Arbor, United States of America

3Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain

4Centro de Investigación Médica Aplicada, University of Navarra, Pamplona, Spain

5Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

6Hematology Service, Hospital Universitario de Navarra, Pamplona, Spain

7Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain

8Cancer and Aging Group, Hospital Universitario Virgen de la Arrixaca, and Instituto Murciano de Investigación Biosanitaria, Murcia, Spain

Find articles by O'Connor, C. in: PubMed | Google Scholar

1Clinical Neuroproteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), UPNA, Pamplona, Spain

2Department of Internal Medicine: Division of Genetic Medicine, The University of Michigan Medical School, Ann Arbor, United States of America

3Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain

4Centro de Investigación Médica Aplicada, University of Navarra, Pamplona, Spain

5Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

6Hematology Service, Hospital Universitario de Navarra, Pamplona, Spain

7Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain

8Cancer and Aging Group, Hospital Universitario Virgen de la Arrixaca, and Instituto Murciano de Investigación Biosanitaria, Murcia, Spain

Find articles by Torres-López, A. in: PubMed | Google Scholar

1Clinical Neuroproteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), UPNA, Pamplona, Spain

2Department of Internal Medicine: Division of Genetic Medicine, The University of Michigan Medical School, Ann Arbor, United States of America

3Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain

4Centro de Investigación Médica Aplicada, University of Navarra, Pamplona, Spain

5Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

6Hematology Service, Hospital Universitario de Navarra, Pamplona, Spain

7Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain

8Cancer and Aging Group, Hospital Universitario Virgen de la Arrixaca, and Instituto Murciano de Investigación Biosanitaria, Murcia, Spain

Find articles by Mateos, M. in: PubMed | Google Scholar

1Clinical Neuroproteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), UPNA, Pamplona, Spain

2Department of Internal Medicine: Division of Genetic Medicine, The University of Michigan Medical School, Ann Arbor, United States of America

3Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain

4Centro de Investigación Médica Aplicada, University of Navarra, Pamplona, Spain

5Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

6Hematology Service, Hospital Universitario de Navarra, Pamplona, Spain

7Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain

8Cancer and Aging Group, Hospital Universitario Virgen de la Arrixaca, and Instituto Murciano de Investigación Biosanitaria, Murcia, Spain

Find articles by Cayuela, M. in: PubMed | Google Scholar

1Clinical Neuroproteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), UPNA, Pamplona, Spain

2Department of Internal Medicine: Division of Genetic Medicine, The University of Michigan Medical School, Ann Arbor, United States of America

3Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain

4Centro de Investigación Médica Aplicada, University of Navarra, Pamplona, Spain

5Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

6Hematology Service, Hospital Universitario de Navarra, Pamplona, Spain

7Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain

8Cancer and Aging Group, Hospital Universitario Virgen de la Arrixaca, and Instituto Murciano de Investigación Biosanitaria, Murcia, Spain

Find articles by Mulero, V. in: PubMed | Google Scholar |

1Clinical Neuroproteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), UPNA, Pamplona, Spain

2Department of Internal Medicine: Division of Genetic Medicine, The University of Michigan Medical School, Ann Arbor, United States of America

3Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain

4Centro de Investigación Médica Aplicada, University of Navarra, Pamplona, Spain

5Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

6Hematology Service, Hospital Universitario de Navarra, Pamplona, Spain

7Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain

8Cancer and Aging Group, Hospital Universitario Virgen de la Arrixaca, and Instituto Murciano de Investigación Biosanitaria, Murcia, Spain

Find articles by Fernández-Irigoyen, J. in: PubMed | Google Scholar

1Clinical Neuroproteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), UPNA, Pamplona, Spain

2Department of Internal Medicine: Division of Genetic Medicine, The University of Michigan Medical School, Ann Arbor, United States of America

3Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain

4Centro de Investigación Médica Aplicada, University of Navarra, Pamplona, Spain

5Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

6Hematology Service, Hospital Universitario de Navarra, Pamplona, Spain

7Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain

8Cancer and Aging Group, Hospital Universitario Virgen de la Arrixaca, and Instituto Murciano de Investigación Biosanitaria, Murcia, Spain

Find articles by Santamaría, E. in: PubMed | Google Scholar

1Clinical Neuroproteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), UPNA, Pamplona, Spain

2Department of Internal Medicine: Division of Genetic Medicine, The University of Michigan Medical School, Ann Arbor, United States of America

3Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain

4Centro de Investigación Médica Aplicada, University of Navarra, Pamplona, Spain

5Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

6Hematology Service, Hospital Universitario de Navarra, Pamplona, Spain

7Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain

8Cancer and Aging Group, Hospital Universitario Virgen de la Arrixaca, and Instituto Murciano de Investigación Biosanitaria, Murcia, Spain

Find articles by Odero, M. in: PubMed | Google Scholar

1Clinical Neuroproteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), UPNA, Pamplona, Spain

2Department of Internal Medicine: Division of Genetic Medicine, The University of Michigan Medical School, Ann Arbor, United States of America

3Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, Spain

4Centro de Investigación Médica Aplicada, University of Navarra, Pamplona, Spain

5Department of Pharmacology, University of Michigan, Ann Arbor, United States of America

6Hematology Service, Hospital Universitario de Navarra, Pamplona, Spain

7Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain

8Cancer and Aging Group, Hospital Universitario Virgen de la Arrixaca, and Instituto Murciano de Investigación Biosanitaria, Murcia, Spain

Find articles by Narla, G. in: PubMed | Google Scholar |

Published September 15, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.205218.
Copyright © 2026, Romero-Murillo et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 15, 2026 - Version history
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Abstract

Cell metabolic rewiring is associated with resistance to venetoclax-azacitidine (Ven-Aza) combination therapy and relapse in acute myeloid leukemia (AML) patients. 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 pro-apoptotic 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 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.

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  • Version 1 (September 15, 2026): In-Press Preview
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