Synergistic action of all-trans retinoic acid and arsenic in the treatment of acute promyelocytic leukaemialeukemia on transcriptional expression and epigenetic regulation

Acute promyelocytic leukaemialeukemia (APL) has been transformed from a highly lethal type of leukaemia to a curable disease in more than 90% of cases, thanks to a treatment combining all-trans retinoic acid (ATRA) , arsenic. The two drugs target the retinoic acid receptor alpha receptor portion moiety and the PML moiety portion of the PML-RARa, the key oncoprotein in the pathogenesis of APL, respectively, resulting in multi-dimensional synergistic actions. It was shown that ATRA is able to restore the expression of PML-RARa-repressed genes and induce terminal differentiation of APL cells, while arsenic tends to exert an effect on protein networks deregulated by PML-RARa and triggers partial cell differentiation or programmed cell death, depending on the doses used. Then, we discovered, with Hugues de The's team, that the two drugs promote PML-RARa degradation through different mechanisms , the simultaneous effect between them allows a faster degradation of oncoprotein as well as an elimination of leukemic stem cells. Recently, we found a particular synergistic mechanism of ATRA and arsenic at the epigenetic level: more efficient regulation of PML-RARa target genes in hyper-acetylated chromatin regions.(c) 2023 Published by Elsevier Masson SAS on behalf of l'Academie nationale de medecine.

Automated summary

Acute promyelocytic leukemia (APL) has been transformed into a curable disease in more than 90% of cases, thanks to a combination treatment of all-trans retinoic acid (ATRA) and arsenic. These two drugs target different components of the PML-RARa oncoprotein and have multi-dimensional synergistic actions. Recent research has also revealed a synergistic mechanism at the epigenetic level.