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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

Author:
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
Source:
Proceedings of the National Academy of Sciences of the United States of America 2013 v.110 no.9 pp. 3495-3500
ISSN:
0027-8424
Subject:
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
Abstract:
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.
Agid:
1785326