ATRA resistance conferred by a clustered subset of hotspot PML::RARA mutations enhancing basal repression rather than precluding transactivation
Year: 2026
Type: article
Abstract: Most acute promyelocytic leukemia (APL), driven by the PML::RARA fusion, are now cured with targeted therapies combining all-trans retinoic acid (ATRA) and arsenic trioxide. Some patients treated with earlier ATRA/chemotherapy regimen developed resistance associated with mutations that most often preclude PML::RARA ATRA-binding. Here, we characterized a subset of clustered mutations associated with ATRA-resistance, but not predicted to affect ATRA binding. Most mutants indeed retained full ligand responsiveness, but displayed a basal super-repressive phenotype which did not result from an increased affinity for known corepressors such as NCoR and SMRT. Our findings suggest these mutations are gain-of-function associated with enhanced interactions with unidentified RARA partners with repressive ability. Similar to ATRA-resistant PLZF::RARA variants, these observations stress the role of persistent transcriptional repression of some retinoic acid target genes in acquired ATRA-resistance.
Source: Haematologica
Institutions: Centre National de la Recherche Scientifique, Inserm, Université de Montpellier, Centre de Biologie Structurale, Shanghai Jiao Tong University, Université Paris Cité, Ruijin Hospital, State Key Laboratory of Medical Genomics, Institut de recherche Saint-Louis, Institut de génétique et de biologie moléculaire et cellulaire, Université de Strasbourg, Collège de France, Centre Interdisciplinaire de Recherche en Biologie, Assistance Publique – Hôpitaux de Paris, Hôpital Saint-Louis
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,157
OpenAlex ID: W7202342261