FDXR upregulation by p63/p73 is a prognostic and therapeutic marker of adult T-cell leukemia/lymphoma
Abstract Infection with HTLV-1 can lead to severe diseases, including adult T-cell leukemia/lymphoma (ATL), for which current therapies are inadequate. Selective elimination of chronically infected cells requires identifying cellular markers dysregulated by HTLV-1 that can be exploited therapeutically. Combining metabolomics and proteomics analyses, we identified increased expression of the mitochondrial enzyme ferredoxin reductase (FDXR) as a hallmark of HTLV-1-infected cells. In patient cells, FDXR upregulation mirrored disease severity, was enriched in proliferating tumour cells and predicted worse ATL prognosis. Mechanistically, FDXR upregulation in ATL cells is driven by the transactivating isoforms of two p53 family members, TAp63 and TAp73, and TAp63 expression is, in turn, induced by the IRF4/BATF3 transcriptional axis. In silico drug susceptibility predictions, followed by targeted cytotoxicity, proliferation and Drug-Seq assays demonstrated that FDXR upregulation is associated with increased sensitivity of ATL cells to repurposed chemotherapeutic agents, particularly fluorouracil. Overall, our findings establish FDXR as a novel biomarker of HTLV-1-associated disease progression and ATL prognosis, elucidate its upstream molecular regulation, and highlight its predictive potential for chemotherapeutic sensitivity of ATL cells.
Authors
- Juliana C. Pereira (ORCID: https://orcid.org/0000-0002-0655-2821)
- Youko Nukui (ORCID: https://orcid.org/0000-0002-7774-4716)
- Hebert Fabrício Culler (ORCID: https://orcid.org/0000-0001-6850-8247)
- Yasunori Kogure (ORCID: https://orcid.org/0000-0003-1158-5131)
- Iart Luca Shytaj (ORCID: https://orcid.org/0000-0002-9980-1275)
- Keisuke Kataoka (ORCID: https://orcid.org/0000-0002-8263-9902)
- Takuro Kameda (ORCID: https://orcid.org/0000-0003-0100-1710)
- Mattia Forcato (ORCID: https://orcid.org/0000-0002-7383-6576)
- Lara Gallucci (ORCID: https://orcid.org/0000-0001-6032-2675)
- Seishi Ogawa (ORCID: https://orcid.org/0000-0002-7778-5374)
- Philip Lewis (ORCID: https://orcid.org/0000-0002-5881-6032)
- Kate J. Heesom (ORCID: https://orcid.org/0000-0002-5418-5392)
- Aaron R. Goldman (ORCID: https://orcid.org/0000-0001-7605-9592)
- Vincent Cantaloube-Ferrieu (ORCID: https://orcid.org/0000-0003-1410-6896)
- Sheila de Oliveira Garcia Mateos (ORCID: https://orcid.org/0000-0001-5416-2724)
- Alex Silva (ORCID: https://orcid.org/0000-0002-6400-5201)
- Kazuya Shimoda (ORCID: https://orcid.org/0000-0002-2555-8188)
- Phoebe Kibble
- Ester Cerdeira Sabino (ORCID: https://orcid.org/0000-0003-2623-5126)
- Marcos Eduardo Souza Abreu (ORCID: https://orcid.org/0009-0006-9670-6957)
- Sophie Shackley
- Maria Josephine
- Luiza Amoroso Lambaz
- Alex Quin
- Aijun Lin
- Sofia Luari Moelas Giuzio
- Felipe Custodio Carvalho dos Santos
- Trusha Ramteke
- Beth Hoare
- Guilherme Lucchesi D Angelo Braz
- Rubens de Assis Santos Sebastiao (ORCID: https://orcid.org/0009-0005-3881-5840)
- Fabio Eudes Leal
- Wujuan Zhang
Institutions
- The Wistar Institute (US)
- University of Miyazaki (JP)
- University of Padua (IT)
- Universidade Municipal de São Caetano do Sul (BR)
- Universidade de São Paulo (BR)
- Keio University (JP)
- Kyoto University (JP)
- University of Bristol (GB)
- National Cancer Centre Japan (JP)
- Instituto Nacional de Câncer - INCA (BR)
- Kindai University (JP)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2026-10-12
- DOI
- https://doi.org/10.1038/s44321-026-00535-0
- Primary Topic
- T-cell and Retrovirus Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00