A synergistic interaction between PRMT5 and LSD1 inhibitors in AML
Acute myeloid leukemia (AML) is a hematopoietic malignancy caused by abnormal proliferation and differentiation of blasts. PRMT5, a methyltransferase that catalyzes symmetric dimethylation of arginine (SDMA) residues, has been implicated in cancer stem cell homeostasis and shown to be a potential therapeutic target in AML. However, given the toxicity of complete PRMT5 inhibition, there is a need to identify effective synergistic therapies. Through a targeted screen of compounds that inhibit key nodes of PRMT5-regulated pathways, we identified a synthetic lethality between inhibition of PRMT5 and LSD1, a lysine demethylase known to affect AML blast differentiation. The two inhibitors broadly reshape the transcriptome of targeted cells and synergize to promote AML differentiation and eventually growth inhibition and apoptosis, in a p53-dependent manner. To leverage this synthetic lethal interaction, we generated new dual compounds to inhibit both enzymes and recapitulated the effects of the drug combination. Our results uncover an unexpected convergence of PRMT5- and LSD1-regulated targets, paving the way for new therapeutic opportunities.
Authors
- Carola Castiello (ORCID: https://orcid.org/0000-0002-7896-5772)
- Jia Yi Fong (ORCID: https://orcid.org/0009-0008-1592-9628)
- Anand D. Jeyasekharan (ORCID: https://orcid.org/0000-0001-9816-6137)
- Roberto Cirilli (ORCID: https://orcid.org/0000-0001-6346-1953)
- Francesco Fiorentino (ORCID: https://orcid.org/0000-0003-3550-1860)
- C.H. Arrowsmith (ORCID: https://orcid.org/0000-0002-4971-3250)
- Andrea Mattevi (ORCID: https://orcid.org/0000-0002-9523-7128)
- Nesteene J. Param (ORCID: https://orcid.org/0000-0002-4276-7563)
- Peggy Scherle (ORCID: https://orcid.org/0000-0003-0783-6815)
- Denis Torre (ORCID: https://orcid.org/0000-0003-4615-223X)
- Yuyuan Han (ORCID: https://orcid.org/0000-0002-3212-875X)
- Elisa Arceci (ORCID: https://orcid.org/0000-0001-9962-7513)
- Tommaso Tabaglio (ORCID: https://orcid.org/0000-0001-6873-3073)
- Luca Pignata (ORCID: https://orcid.org/0000-0002-4903-8160)
- Marco Barone (ORCID: https://orcid.org/0000-0001-7184-2940)
- Elisabetta Di Bello (ORCID: https://orcid.org/0000-0002-9257-7485)
- Megan Schwarz (ORCID: https://orcid.org/0000-0001-8715-2039)
- Manikandan Lakshmanan (ORCID: https://orcid.org/0000-0001-5673-7392)
- Ernesto Guccione (ORCID: https://orcid.org/0000-0001-7764-5307)
- Sérgio Valente (ORCID: https://orcid.org/0000-0002-2241-607X)
- Chiara Lambona (ORCID: https://orcid.org/0000-0002-3415-4126)
- Nayeli Gutiérrez-Trejo
- Dave Keng Boon Wee
- Antonello Mai
- Koichi Ito
- Hansjörg Habisch
- Pierre-Alexis Goy
- Steven Ndoye
- Tobias Madl
Institutions
- Agency for Science, Technology and Research (SG)
- National University of Singapore (SG)
- Toronto Public Health (CA)
- Medical University of Graz (AT)
- University of Pavia (IT)
- Istituto Superiore di Sanità (IT)
- National University Cancer Institute, Singapore (SG)
- BioTechMed-Graz (AT)
- National University Hospital (SG)
- Institute of Molecular and Cell Biology (SG)
- Sapienza University of Rome (IT)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Science Advances
- Published
- 2026-03-27
- DOI
- https://doi.org/10.1126/sciadv.aea4059
- Primary Topic
- Cancer-related gene regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.00