8-CPT-cAMP/all-trans retinoic acid targets t(11;17) acute promyelocytic leukemia through enhanced cell differentiation and PLZF/RARa degradation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-02, Vol.110 (9), p.3495
• Main Authors: Jiao, Bo, Ren, Zhi-Hong, Liu, Ping, Chen, Li-Juan, Shi, Jing-Yi, Dong, Ying, Ablain, Julien, Shi, Lin, Gao, Li, Hu, Jun-Pei, Ren, Rui-Bao, de Thé, Hugues, Chen, Zhu, Chen, Sai-Juan
• Format: Article
• Language: English
• Subjects: Biodegradation; Cells; Chromatin; Leukemia; Phosphorylation; Proteins
• ISSN: 0027-8424; 1091-6490

The refractoriness of acute promyelocytic leukemia (APL) with t(11;17)(q23;q21) to all-trans retinoic acid (ATRA)-based therapy concerns clinicians and intrigues basic researchers. By using a murine leukemic model carrying both promyelocytic leukemia zinc finger/retinoic acid receptor-α (PLZF/RARα) and RARα/PLZF fusion genes, we discovered that 8-chlorophenylthio adenosine-3', 5'-cyclic monophosphate (8-CPT-cAMP) enhances cellular differentiation and improves gene trans-activation by ATRA in leukemic blasts. Mechanistically, in combination with ATRA, 8-CPT-cAMP activates PKA, causing phosphorylation of PLZF/RARα at Ser765 and resulting in increased dissociation of the silencing mediator for retinoic acid and thyroid hormone receptors/nuclear receptor corepressor from PLZF/RARα. This process results in changes of local chromatin and transcriptional reactivation of the retinoic acid pathway in leukemic cells. Meanwhile, 8-CPT-cAMP also potentiated ATRA-induced degradation of PLZF/RARα through its Ser765 phosphorylation. In vivo treatment of the t(11;17) APL mouse model demonstrated that 8-CPT-cAMP could significantly improve the therapeutic effect of ATRA by targeting a leukemia-initiating cell activity. This combined therapy, which induces enhanced differentiation and oncoprotein degradation, may benefit t(11;17) APL patients. [PUBLICATION ABSTRACT]