RAR?2 and PML-RAR similarities in the control of basal and retinoic acid induced myeloid maturation of acute myeloid leukemia cells.

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 RAR?. PML-RAR is responsible for the differentiation block of the leukemic blast. Besides PML-RAR, two endogenous RAR? proteins are present in APL blasts, i.e. RAR?1 and RAR?2. We developed different cell populations characterized by PML-RAR, RAR?2 and RAR?1 knock-down in the APL-derived NB4 cell-line. Unexpectedly, silencing of PML-RAR and RAR?2 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 RAR?2 causes also similar perturbations in the whole genome gene-expression profiles of vehicle and ATRA treated NB4 cells. Unlike PML-RAR and RAR?2, RAR?1 knock-down blocks ATRA-dependent induction of several granulocytic differentiation markers. Many of the effects on myeloid differentiation are confirmed by over-expression of RAR?2 in NB4 cells. RAR?2 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 RAR?1, PML-RAR and RAR?2 exert opposite effects on APL-cell differentiation. These contrasting actions may be related to the fact that both PML-RAR and RAR?2 interact with and inhibit the transcriptional activity of RAR?1. 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 RAR?1.

SUBMITTER: Gianni M 

PROVIDER: S-EPMC5514891 | biostudies-other | 2017 Jun

REPOSITORIES: biostudies-other