Vesicular trafficking is a key determinant of the statin response in acute myeloid leukemia
| Autor: | Réjean Ruel, Deanne Gracias, Bernhard Lehnertz, Jasmin Coulombe-Huntington, Geneviève Boucher, Richard Bisaillon, Guy Sauvageau, Sébastien Lemieux, Marie-Eve Bordeleau, Tara MacRae, Thierry Bertomeu, Nadine Mayotte, Josée Hébert, Céline Moison, Anne Marinier, Patrick Gendron, Mike Tyers, Isabel Boivin, Jana Krosl, Irène Baccelli, Frédéric Barabé, Rodrigo Mendoza-Sanchez, Vincent-Philippe Lavallée, Caroline Pabst, Nandita Noronha |
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| Rok vydání: | 2022 |
| Předmět: |
Statin
medicine.drug_class hemic and lymphatic diseases medicine Humans cardiovascular diseases Viability assay neoplasms business.industry Mechanism (biology) nutritional and metabolic diseases Myeloid leukemia Hematology Stimulus Report Chemical screening Clinical trial Leukemia Myeloid Acute Mechanism of action Cancer research lipids (amino acids peptides and proteins) Rab Hydroxymethylglutaryl-CoA Reductase Inhibitors medicine.symptom business |
| Zdroj: | Blood Advances |
| ISSN: | 2473-9537 2473-9529 |
| Popis: | Key Points Inhibition of RAB protein function mediates the anti–acute myeloid leukemia activity of statins.Statin sensitivity is associated with enhanced vesicle-mediated traffic. Visual Abstract Cholesterol homeostasis has been proposed as one mechanism contributing to chemoresistance in AML and hence, inclusion of statins in therapeutic regimens as part of clinical trials in AML has shown encouraging results. Chemical screening of primary human AML specimens by our group led to the identification of lipophilic statins as potent inhibitors of AMLs from a wide range of cytogenetic groups. Genetic screening to identify modulators of the statin response uncovered the role of protein geranylgeranylation and of RAB proteins, coordinating various aspect of vesicular trafficking, in mediating the effects of statins on AML cell viability. We further show that statins can inhibit vesicle-mediated transport in primary human specimens, and that statins sensitive samples show expression signatures reminiscent of enhanced vesicular trafficking. Overall, this study sheds light into the mechanism of action of statins in AML and identifies a novel vulnerability for cytogenetically diverse AML. |
| Databáze: | OpenAIRE |
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