RARα2 and PML-RAR similarities in the control of basal and retinoic acid induced myeloid maturation of acute myeloid leukemia cells
| Autor: | Gianmaria Borleri, Gabriela Paroni, Alessandro Rambaldi, Maurizio Gianni, Mami Kurosaki, Adriana Zanetti, Maddalena Fratelli, Marco Bolis, Enrico Garattini, Cécile Rochette-Egly, Mineko Terao |
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| Přispěvatelé: | IRCCS - Istituto di Ricerche Farmacologiche 'Mario Negri' [Milan, Italy], Azienda Ospedaliera Ospedale Papa Giovanni XXIII [Bergamo, Italy], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), univOAK, Archive ouverte |
| Rok vydání: | 2016 |
| Předmět: |
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology
0301 basic medicine Myeloid Oncogene Proteins Fusion Cellular differentiation Retinoic acid chemistry.chemical_compound 0302 clinical medicine Aml Chlorocebus aethiops retinoic acid Gene Expression Regulation Leukemic Retinoic Acid Receptor alpha Myeloid leukemia Cell Differentiation [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology Cell biology Leukemia medicine.anatomical_structure Oncology Leukemia Myeloid 030220 oncology & carcinogenesis Acute Disease COS Cells embryonic structures [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN] RNA Interference Research Paper medicine.drug Acute promyelocytic leukemia Cell Survival Antineoplastic Agents HL-60 Cells Tretinoin [SDV.CAN]Life Sciences [q-bio]/Cancer Biology Pml-rar 03 medical and health sciences [SDV.CAN] Life Sciences [q-bio]/Cancer Cell Line Tumor [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN] medicine Animals Humans RARalpha2 neoplasms organic chemicals RARα2 medicine.disease biological factors 030104 developmental biology chemistry Retinoic acid receptor alpha silencing Immunology |
| Zdroj: | Oncotarget Oncotarget, 2017, 8 (23), pp.37041-37060. ⟨10.18632/oncotarget.10556⟩ |
| ISSN: | 1949-2553 |
| Popis: | Treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) is the first example of targeted therapy. In fact, the oncogenic fusion-protein (PML-RAR) typical of this leukemia contains the retinoid-nuclear-receptor RARalpha. PML-RAR is responsible for the differentiation block of the leukemic blast. Besides PML-RAR, two endogenous RARalpha proteins are present in APL blasts, i.e. RARalpha1 and RARalpha2. We developed different cell populations characterized by PML-RAR, RARalpha2 and RARalpha1 knock-down in the APL-derived NB4 cell-line. Unexpectedly, silencing of PML-RAR and RARalpha2 results in similar increases in the constitutive expression of several granulocytic differentiation markers. This is accompanied by enhanced expression of the same granulocytic markers upon exposure of the NB4 blasts to ATRA. Silencing of PML-RAR and RARalpha2 causes also similar perturbations in the whole genome gene-expression profiles of vehicle and ATRA treated NB4 cells. Unlike PML-RAR and RARalpha2, RARalpha1 knock-down blocks ATRA-dependent induction of several granulocytic differentiation markers. Many of the effects on myeloid differentiation are confirmed by over-expression of RARalpha2 in NB4 cells. RARalpha2 action on myeloid differentiation does not require the presence of PML-RAR, as it is recapitulated also upon knock-down in PML-RAR-negative HL-60 cells. Thus, relative to RARalpha1, PML-RAR and RARalpha2 exert opposite effects on APL-cell differentiation. These contrasting actions may be related to the fact that both PML-RAR and RARalpha2 interact with and inhibit the transcriptional activity of RARalpha1. The interaction surface is located in the carboxy-terminal domain containing the D/E/F regions and it is influenced by phosphorylation of Ser-369 of RARalpha1. |
| Databáze: | OpenAIRE |
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