ATRA resistance conferred by a clustered subset of hotspot PML::RARA mutations enhancing basal repression rather than precluding transactivation
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.
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BibTeX
@article{barbosa2026atra,
title = {{ATRA resistance conferred by a clustered subset of hotspot PML::RARA mutations enhancing basal repression rather than precluding transactivation}},
author = {Glauce M Barbosa and Hao Yuan and Izabella Tambones and Roland H Stote and Hsin Chieh Wu and Hugues de Thé and Albane Le Maire and Marie-Claude C Geoffroy},
journal = {Haematologica},
year = {2026},
month = aug,
doi = {10.3324/haematol.2025.300279},
url = {https://hal.science/hal-05775581v1},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - ATRA resistance conferred by a clustered subset of hotspot PML::RARA mutations enhancing basal repression rather than precluding transactivation
AU - Glauce M Barbosa
AU - Hao Yuan
AU - Izabella Tambones
AU - Roland H Stote
AU - Hsin Chieh Wu
AU - Hugues de Thé
AU - Albane Le Maire
AU - Marie-Claude C Geoffroy
PY - 2026
DA - 2026/08/13
JO - Haematologica
DO - 10.3324/haematol.2025.300279
UR - https://hal.science/hal-05775581v1
AB - 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.
SN - 0390-6078
SN - 1592-8721
ER -