DEK::NUP214 acts as an XPO1-dependent transcriptional activator of essential leukemia genes
The t(6;9)(p22.3;q34.1) translocation/DEK::NUP214 fusion protein defines a distinct subgroup of younger AML patients classified as a separate disease entity by the World Health Organization. DEK is a nuclear factor with multifunctional roles, including gene regulation, while its fusion partner, NUP214, plays a pivotal role in nuclear export by interacting with transport receptors such as XPO1. However, the precise mechanism by which DEK::NUP214 drives leukemia remains unclear. A comprehensive multi-omics comparison of 57 AML primary samples (including whole genome sequencing, targeted sequencing, transcriptomics, and drug screening with >500 compounds) revealed that t(6;9) cases display a selective response to XPO1 inhibitors (Selinexor & Eltanexor) and a distinct transcriptomic signature characterized by the overexpression of FOXC1 and HOX genes that are key leukemia mediators. CUT&RUN experiments demonstrated the direct binding of DEK::NUP214 to the promoters of FOXC1 and HOXA/B clusters. Strikingly, the expression of these genes and the binding of DEK::NUP214 to their regulatory regions were selectively reduced upon XPO1 inhibition in t(6;9) cells. Altogether, these results identified a novel function of DEK::NUP214 as an XPO1-dependent transcriptional activator of key leukemia drivers and provide a rationale to explore the use of XPO1 inhibitors in this patient population.
Authors
- Doriana Di Bella
- Juho J. Miettinen (ORCID: https://orcid.org/0000-0002-3987-1693)
- Csaba Bödör (ORCID: https://orcid.org/0000-0002-0729-692X)
- Fadimana Kaya (ORCID: https://orcid.org/0000-0003-3173-1706)
- Dominique A. Bonnet (ORCID: https://orcid.org/0000-0002-4735-5226)
- Findlay Bewicke‐Copley (ORCID: https://orcid.org/0000-0003-1292-7965)
- Marianne Grantham
- Pilar Llamas (ORCID: https://orcid.org/0000-0002-8552-3219)
- Naeem Khan (ORCID: https://orcid.org/0000-0002-0379-4622)
- Sylvie Freeman (ORCID: https://orcid.org/0000-0003-1869-180X)
- Özgen Deniz (ORCID: https://orcid.org/0000-0001-7268-1923)
- James D. Cavenagh
- Guy Sauvageau (ORCID: https://orcid.org/0000-0002-4333-7266)
- Joseph Saad (ORCID: https://orcid.org/0000-0001-7701-0328)
- Alexis Nolin-Lapalme (ORCID: https://orcid.org/0000-0001-7919-2508)
- Pedro R. Cutillas (ORCID: https://orcid.org/0000-0002-3426-2274)
- Josée Hébert (ORCID: https://orcid.org/0000-0002-2267-1353)
- David Taussig (ORCID: https://orcid.org/0000-0002-9621-0146)
- Ana Rio‐Machín (ORCID: https://orcid.org/0000-0001-6733-9752)
- Vincent‐Philippe Lavallée (ORCID: https://orcid.org/0000-0001-9095-0066)
- Caroline A. Heckman (ORCID: https://orcid.org/0000-0002-4324-8706)
- Jiexin Zheng (ORCID: https://orcid.org/0000-0003-4435-2254)
- John G. Gribben (ORCID: https://orcid.org/0000-0002-8505-7430)
- Krister Wennerberg (ORCID: https://orcid.org/0000-0002-1352-4220)
- Pedro Casado (ORCID: https://orcid.org/0000-0002-4207-9349)
- Jean‐Baptiste Cazier (ORCID: https://orcid.org/0000-0001-7581-9051)
- Céline Philippe (ORCID: https://orcid.org/0000-0002-8546-3893)
- Szilvia Krizsán (ORCID: https://orcid.org/0000-0002-1782-9275)
- Sébastien Lemieux (ORCID: https://orcid.org/0000-0001-5477-1386)
- Kevin Rouault‐Pierre (ORCID: https://orcid.org/0000-0001-7671-7364)
- Jude Fitzgibbon
- Éric Audemard (ORCID: https://orcid.org/0000-0002-1661-896X)
- Florian Grebien (ORCID: https://orcid.org/0000-0003-4289-2281)
- Jun Wang (ORCID: https://orcid.org/0000-0003-2509-9599)
- Janet Matthews
- Alun Parsons
- Eve Leddy
Institutions
- Semmelweis University (HU)
- University of Copenhagen (DK)
- St Bartholomew's Hospital (GB)
- University College London Hospitals NHS Foundation Trust (GB)
- Austrian Academy of Sciences (AT)
- University of Veterinary Medicine Vienna (AT)
- Inserm (FR)
- Queen Mary University of London (GB)
- Barts Health NHS Trust (GB)
- The Francis Crick Institute (GB)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Hôpital Maisonneuve-Rosemont (CA)
- Blood Cancer UK (GB)
- Oncogenesis Stress Signaling (FR)
- Institute for Research in Immunology and Cancer (CA)
- Centre Eugène Marquis (FR)
- St Anna Children's Hospital (AT)
- CeMM Research Center for Molecular Medicine (AT)
- Hospital Universitario Fundación Jiménez Díaz (ES)
- Institute for Molecular Medicine Finland (FI)
- St. Anna Children's Cancer Research Institute
- University College London (GB)
- Universidad Autónoma de Madrid (ES)
- Université de Montréal (CA)
- University of Birmingham (GB)
Publication Details
- Journal
- Leukemia
- Published
- 2025-04-09
- DOI
- https://doi.org/10.1038/s41375-025-02593-8
- Citations
- 5
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 8.85
Funders
- Cancer Research Institute
- Helsingin Yliopisto
- European Hematology Association
- Genome Canada
- Queen Mary University of London
- Francis Crick Institute
- Barts Charity
- Cancer Research UK
- Kay Kendall Leukaemia Fund
- University College London
- Institut National de la Santé et de la Recherche Médicale
- Österreichischen Akademie der Wissenschaften
- Semmelweis Egyetem
- Université de Montréal
- University College London Hospitals NHS Foundation Trust
- Veterinärmedizinische Universität Wien
- Centre hospitalier universitaire Sainte-Justine
- Barts Health NHS Trust
- Directorate for Biological Sciences
- Helsinki Institute of Life Science, Helsingin Yliopisto