A Pin1/PML/P53 axis activated by retinoic acid in NPM-1c acute myeloid leukemia
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Ferrata Storti Foundation
Abstract
Retinoic acid (RA) was proposed to increase survival of chemotherapy-treated patients with nucleophosmin-1 (NPM-1c)-mutated acute myeloid leukemia. We reported that, ex vivo, RA triggers NPM-1c degradation, P53 activation and growth arrest. PML organizes domains that control senescence or proteolysis. Here, we demonstrate that PML is required to initiate RA-driven NPM-1c degradation, P53 activation and cell death. Mechanistically, RA enhances PML basal expression through inhibition of activated Pin1, prior to NPM-1c degradation. Such PML induction drives P53 activation, favoring blast response to chemotherapy or arsenic in vivo. This RA/PML/P53 cascade could mechanistically explain RA-facilitated chemotherapy response in patients with NPM-1c mutated acute myeloid leukemia. ©2021 Ferrata Storti Foundation
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Humans, Leukemia, myeloid, acute, Leukemia, promyelocytic, acute, Nima-interacting peptidylprolyl isomerase, Nuclear proteins, Oncogene proteins, fusion, Tretinoin, Tumor suppressor protein p53, Antibody, Arsenic trioxide, Cytarabine, Doxorubicin, Methylcellulose, Nucleophosmin 1c, Peptidyl prolyl cis trans isomerase nima interacting 1, Peptidyl prolyl cis trans isomerase nima interacting 1 antibody, Protein, Protein p53, Puromycin, Receptor type tyrosine protein phosphatase c, Retinoic acid, Unclassified drug, Nima interacting peptidylprolyl isomerase, Nuclear protein, Oncoprotein, Pin1 protein, human, Acute myeloid leukemia, Animal experiment, Animal model, Article, Cancer chemotherapy, Cell death, Cell differentiation, Cell growth assay, Cell proliferation, Colony formation, Confocal microscopy, Controlled study, Crispr cas system, Densitometry, Down regulation, Flow cytometry, Gene knockdown, Gene overexpression, Genetic transfection, Human, Human cell, Immunoblotting, Immunofluorescence, Microarray analysis, Mouse, Nonhuman, Oci-aml-2 cell line, Oci-aml-3 cell line, Polymerase chain reaction, Promyelocytic leukemia, Protein degradation, Rna isolation, Tumor xenograft, Western blotting, Genetics, Metabolism