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Cited by 45Retinoids in leukemia and cellular processesCancer-related Molecular PathwaysProtein Structure and Dynamics

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Structural Basis of PML-RARA Oncoprotein Targeting by Arsenic Unravels a Cysteine Rheostat Controlling PML Body Assembly and Function

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Bercier, Pierre, Wang, Qian Qian, Zang, Ning, Zhang, Jie, Yang, Chang, Maimaitiyiming, Yasen, Abou-Ghali, Majdouline, Berthier, Caroline, Wu, Chengchen, Niwa-Kawakita, Michiko, Dirami, Thassadite, Geoffroy, Marie-Claude, Ferhi, Omar, Quentin, Samuel, Benhenda, Shirine, Ogra, Yasumitsu, Gueroui, Zoher, Zhou, Chun, Naranmandura, Hua, de Thé, Hugues, Lallemand-Breitenbach, Valérie·2023·Cancer Discovery
DOI 10.1158/2159-8290.cd-23-0453PMC PMC10714139

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Abstract

PML nuclear bodies (NB) are disrupted in PML-RARA–driven acute promyelocytic leukemia (APL). Arsenic trioxide (ATO) cures 70% of patients with APL, driving PML-RARA degradation and NB reformation. In non-APL cells, arsenic binding onto PML also amplifies NB formation. Yet, the actual molecular mechanism(s) involved remain(s) elusive. Here, we establish that PML NBs display some features of liquid–liquid phase separation and that ATO induces a gel-like transition. PML B-box-2 structure reveals an alpha helix driving B2 trimerization and positioning a cysteine trio to form an ideal arsenic-binding pocket. Altering either of the latter impedes ATO-driven NB assembly, PML sumoylation, and PML-RARA degradation, mechanistically explaining clinical ATO resistance. This B2 trimer and the C213 trio create an oxidation-sensitive rheostat that controls PML NB assembly dynamics and downstream signaling in both basal state and during stress response. These findings identify the structural basis for arsenic targeting of PML that could pave the way to novel cancer drugs. Significance: Arsenic curative effects in APL rely on PML targeting. We report a PML B-box-2 structure that drives trimer assembly, positioning a cysteine trio to form an arsenic-binding pocket, which is disrupted in resistant patients. Identification of this ROS-sensitive triad controlling PML dynamics and functions could yield novel drugs. See related commentary by Salomoni, p. 2505. This article is featured in Selected Articles from This Issue, p. 2489

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Metadata

Authors
Bercier, P., Wang, Q. Q., Zang, N., Zhang, J., Yang, C., Maimaitiyiming, Y., Abou-Ghali, M., Berthier, C., Wu, C., Niwa-Kawakita, M., Dirami, T., Geoffroy, M.-C., Ferhi, O., Quentin, S., Benhenda, S., Ogra, Y., Gueroui, Z., Zhou, C., Naranmandura, H., de Thé, H., & Lallemand-Breitenbach, V.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • First Affiliated Hospital Zhejiang University (CN)
  • Sir Run Run Shaw Hospital (CN)
  • 1Center for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS, INSERM, Université PSL, Paris, France.
  • Chiba University (JP)
Corresponding author
  • Zhou, Chun
  • Naranmandura, Hua
  • de Thé, Hugues
  • Lallemand-Breitenbach, Valérie
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2023-09-01
Volume
13
Issue
12
Pages
2548-2565
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
DOI
10.1158/2159-8290.cd-23-0453
PMC
PMC10714139
OpenAlex
W4386346642
Cited by
45
References
4
Citations by year
2026: 14 · 2025: 15 · 2024: 14 · 2023: 2
FWCI
4.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Discovery (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, public-domain)
Funders
  • Institut National de la Santé et de la Recherche Médicale
  • Institut des sciences biologiques
  • Collège de France
  • Alliance Nationale pour les Sciences de la Vie et de la Santé (PCSI C22028DS)
  • Fondation du Collège de France
  • European Research Council (785917&#x2013, PML-THERAPY)
  • Sjöbergstiftelsen (Awards 2018)
  • National Natural Science Foundation of China (82170143, 31971125)
  • Zhejiang University Student Science and Technology Innovation Activity Plan (2020R01006)
  • Fondation ARC pour la Recherche sur le Cancer
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
PML nuclear bodies, PML-RARA fusion, acute promyelocytic leukemia, arsenic trioxide, liquid-liquid phase separation, arsenic resistance, oxidative stress response, protein structure
MeSH terms
Arsenic Trioxide, Promyelocytic Leukemia Nuclear Bodies, Arsenic, Arsenicals, Cysteine, Humans, Oxides, Leukemia, Promyelocytic, Acute, Oncogene Proteins, Oncogene Proteins, Fusion

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