RARα2 and PML-RAR similarities in the control of basal and retinoic acid induced myeloid maturation of acute myeloid leukemia cells
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Maurizio Gianni1, Maddalena Fratelli1, Marco Bolis1, Mami Kurosaki1, Adriana Zanetti1, Gabriela Paroni1, Alessandro Rambaldi2, Gianmaria Borleri2, Cecile Rochette-Egly3, Mineko Terao1 and Enrico Garattini1
1Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri”, 20156 Milano, Italy
2Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, 24127 Bergamo, Italy
3Department of Functional Genomics and Cancer, IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), INSERM, U964, CNRS, UMR7104, Université de Strasbourg, 67404 Illkirch Cedex, France
Enrico Garattini, email: [email protected]
Keywords: RARα2, retinoic acid, AML, silencing, PML-RAR
Received: May 16, 2016 Accepted: July 01, 2016 Published: July 13, 2016
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 RARα. PML-RAR is responsible for the differentiation block of the leukemic blast. Besides PML-RAR, two endogenous RARα proteins are present in APL blasts, i.e. RARα1 and RARα2. We developed different cell populations characterized by PML-RAR, RARα2 and RARα1 knock-down in the APL-derived NB4 cell-line. Unexpectedly, silencing of PML-RAR and RARα2 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 RARα2 causes also similar perturbations in the whole genome gene-expression profiles of vehicle and ATRA treated NB4 cells. Unlike PML-RAR and RARα2, RARα1 knock-down blocks ATRA-dependent induction of several granulocytic differentiation markers. Many of the effects on myeloid differentiation are confirmed by over-expression of RARα2 in NB4 cells. RARα2 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 RARα1, PML-RAR and RARα2 exert opposite effects on APL-cell differentiation. These contrasting actions may be related to the fact that both PML-RAR and RARα2 interact with and inhibit the transcriptional activity of RARα1. 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 RARα1.
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