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

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
Proceedings of the National Academy of Sciences of the United States of America 2013 v.110 no.9 pp. 3495-3500
animal models, cAMP-dependent protein kinase, cell differentiation, chromatin, dissociation, genes, leukemia, mice, oncogene proteins, patients, phosphorylation, researchers, retinoic acid, therapeutics, thyroid hormone receptors, transcription (genetics), zinc finger motif
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.