Pivotal role of the endoplasmic reticulum stress-related XBP1s/miR-22/SIRT1 axis in acute myeloid leukemia apoptosis and response to chemotherapy.


Journal

Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895

Informations de publication

Date de publication:
22 Jun 2024
Historique:
received: 19 01 2024
accepted: 17 06 2024
revised: 13 06 2024
medline: 23 6 2024
pubmed: 23 6 2024
entrez: 22 6 2024
Statut: aheadofprint

Résumé

Malignant growth relies on rapid protein synthesis frequently leading to endoplasmic reticulum (ER) overload and accumulation of unfolded or misfolded protein in this cellular compartment. In the ER, protein homeostasis is finely regulated by a mechanism called the unfolded protein response (UPR), involving the activation of signalization pathways mediated by three transmembrane proteins, namely PERK, IRE1 and ATF6. IRE1 endoribonuclease activation leads in particular to the splicing of the cytosolic mRNA encoding the key UPR-specific transcription factor XBP1s. Our study shows that sustained activation of XBP1s expression in acute myeloid leukemia (AML) cells induces apoptosis in vitro and in vivo, whereas a moderate XBP1s expression sensitizes cells to chemotherapeutic treatments. ChIP-seq experiments identified specific XBP1s target genes including the MIR22HG lncRNA, the precursor transcript of microRNA-22-3p. miR-22-3p upregulation by XBP1s or forced expression of miR-22 significantly decreases cell's viability and sensitizes leukemic cells to chemotherapy. We found that miR-22-3p intracellular effects result at least partially from the targeting of the mRNA encoding the deacetylase sirtuin-1 (SIRT1), a well-established pro-survival factor. Therefore, this novel XBP1s/miR-22/SIRT1 axis identified could play a pivotal role in the proliferation and chemotherapeutic response of leukemic cells.

Identifiants

pubmed: 38909090
doi: 10.1038/s41375-024-02321-8
pii: 10.1038/s41375-024-02321-8
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : Association Laurette Fugain (Laurette Fugain)
ID : ALF2018/03
Organisme : Kay Kendall Leukaemia Fund (KKLF)
ID : KKL1149
Organisme : Academy of Medical Sciences
ID : SBF004\1099
Pays : United Kingdom

Informations de copyright

© 2024. The Author(s).

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Auteurs

Céline Philippe (C)

Barts Cancer Institute, Queen Mary University of London, London, UK. celine.philippe@inserm.fr.

Manon Jaud (M)

Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Kelly Féral (K)

Centre de Recherches en Cancérologie de Toulouse (CRCT), INSERM UMR-1037, CNRS UMR-5071, Université de Toulouse, Toulouse, France.

Alexandre Gay (A)

Centre de Recherches en Cancérologie de Toulouse (CRCT), INSERM UMR-1037, CNRS UMR-5071, Université de Toulouse, Toulouse, France.

Loïc Van Den Berghe (L)

Vectorology Platform, CRCT INSERM UMR-1037 Technological Pole, F-31037, Toulouse, France.

Manon Farce (M)

Flow Cytometry and Cell Sorting Platform, CRCT INSERM UMR-1037 Technological Pole, F-31037, Toulouse, France.

Marina Bousquet (M)

Centre de Recherches en Cancérologie de Toulouse (CRCT), INSERM UMR-1037, CNRS UMR-5071, Université de Toulouse, Toulouse, France.

Stéphane Pyronnet (S)

Centre de Recherches en Cancérologie de Toulouse (CRCT), INSERM UMR-1037, CNRS UMR-5071, Université de Toulouse, Toulouse, France.

Laurent Mazzolini (L)

Centre de Recherches en Cancérologie de Toulouse (CRCT), INSERM UMR-1037, CNRS UMR-5071, Université de Toulouse, Toulouse, France.

Kevin Rouault-Pierre (K)

Barts Cancer Institute, Queen Mary University of London, London, UK.

Christian Touriol (C)

Centre de Recherches en Cancérologie de Toulouse (CRCT), INSERM UMR-1037, CNRS UMR-5071, Université de Toulouse, Toulouse, France. christian.touriol@inserm.fr.

Classifications MeSH