RARalpha2 and PML-RAR similarities in the control of basal and retinoic acid induced myeloid maturation of acute myeloid leukemia cells - Archive ouverte HAL Access content directly
Journal Articles Oncotarget Year : 2017

RARalpha2 and PML-RAR similarities in the control of basal and retinoic acid induced myeloid maturation of acute myeloid leukemia cells

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Abstract

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.
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Dates and versions

hal-03677831 , version 1 (08-12-2022)

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Maurizio Gianni, Maddalena Fratelli, Marco Bolis, Mami Kurosaki, Adriana Zanetti, et al.. RARalpha2 and PML-RAR similarities in the control of basal and retinoic acid induced myeloid maturation of acute myeloid leukemia cells. Oncotarget, 2017, 8 (23), pp.37041-37060. ⟨10.18632/oncotarget.10556⟩. ⟨hal-03677831⟩
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