title: 8-CPT-cAMP/all-trans retinoic acid targets t(11;17) acute promyelocytic leukemia through enhanced cell differentiation and PLZF/RARα degradation.
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.
authors: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital,  Shanghai Jiao Tong University School of Medicine, Shanghai 200025,  China.
authors: Bo
authors: B
authors: Jiao
authors: Zhi-Hong
authors: ZH
authors: Ren
authors: Ping
authors: P
authors: Liu
authors: Li-Juan
authors: LJ
authors: Chen
authors: Jing-Yi
authors: JY
authors: Shi
authors: Ying
authors: Y
authors: Dong
authors: Julien
authors: J
authors: Ablain
authors: Lin
authors: L
authors: Shi
authors: Li
authors: L
authors: Gao
authors: Jun-Pei
authors: JP
authors: Hu
authors: Rui-Bao
authors: RB
authors: Ren
authors: Hugues
authors: H
authors: de Thé
authors: Zhu
authors: Z
authors: Chen
authors: Sai-Juan
authors: SJ
authors: Chen
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D056985:Nuclear Receptor Co-Repressor 2 / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D013873:Thionucleotides / Q000494:pharmacology / Q000627:therapeutic use*; D014178:Translocation, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C539131:Ncor2 protein, mouse; D056985:Nuclear Receptor Co-Repressor 2; D015514:Oncogene Proteins, Fusion; C492209:PLZF-RARalpha fusion protein, mouse; D013873:Thionucleotides; D010768:Phosphoserine; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D014212:Tretinoin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
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