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Updated: Aug 19, 2026

Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

ATRA resistance conferred by a clustered subset of hotspot PML::RARA mutations enhancing basal repression rather than

Glauce M Barbosa1, Hao Yuan2, Izabella Tambones1

  • 1Université de Montpellier, Centre de Biologie Structurale (CBS), CNRS UMR5048-INSERM U1054, Montpellier.

Haematologica
|August 18, 2026
PubMed

Insights

Acute promyelocytic leukemia (APL) treatments combining all-trans retinoic acid (ATRA) are effective. New research reveals specific mutations can cause ATRA resistance by enhancing interactions with unidentified RARA partners, leading to persistent transcriptional repression.

Area of Science:

  • Hematology
  • Molecular Biology
  • Cancer Research

Background:

  • Acute promyelocytic leukemia (APL) is driven by the PML::RARA fusion gene.
  • Targeted therapies combining all-trans retinoic acid (ATRA) and arsenic trioxide have high cure rates for APL.
  • Earlier ATRA/chemotherapy regimens led to resistance in some patients, often due to mutations affecting PML::RARA ATRA-binding.

Purpose of the Study:

  • To characterize clustered mutations associated with ATRA resistance that do not affect ATRA binding.
  • To investigate the mechanism behind ATRA resistance in APL.
  • To explore the role of transcriptional repression in acquired ATRA resistance.

Main Methods:

  • Characterization of clustered mutations in PML::RARA.
  • Assessment of ligand responsiveness and corepressor binding (NCoR, SMRT).
  • Analysis of basal super-repressive phenotype in resistant mutants.

Main Results:

  • A subset of ATRA-resistance mutations retained full ligand responsiveness.
  • These mutants exhibited a basal super-repressive phenotype.
  • The super-repression did not stem from increased affinity for known corepressors (NCoR, SMRT).
  • Mutations suggest gain-of-function via enhanced interactions with unidentified repressive RARA partners.

Conclusions:

  • Acquired ATRA resistance in APL can occur through mechanisms independent of direct ATRA-binding disruption.
  • Mutations conferring ATRA resistance may involve enhanced interactions with novel repressive RARA partners.
  • Persistent transcriptional repression of retinoic acid target genes plays a significant role in acquired ATRA resistance, similar to PLZF::RARA variants.

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