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: Bo Jiao, Zhi-Hong Ren, Ping Liu, Li-Juan Chen, Jing-Yi Shi, Ying Dong, Julien Ablain, Lin Shi, Li Gao, Jun-Pei Hu, Rui-Bao Ren, Hugues de Thé, Zhu Chen, Sai-Juan Chen
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 9 Pg. 3495-500 (Feb 26 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 23382200 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ncor2 protein, mouse
• Nuclear Receptor Co-Repressor 2
• Oncogene Proteins, Fusion
• PLZF-RARalpha fusion protein, mouse
• Thionucleotides
• Phosphoserine
• 8-((4-chlorophenyl)thio)cyclic-3',5'-AMP
• Tretinoin
• Cyclic AMP
• Cyclic AMP-Dependent Protein Kinases

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Cell Differentiation (drug effects, genetics)
• Chromosomes, Human, Pair 11 (genetics)
• Chromosomes, Human, Pair 17 (genetics)
• Cyclic AMP (analogs & derivatives, pharmacology, therapeutic use)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Female
• Humans
• Leukemia, Promyelocytic, Acute (drug therapy, genetics, pathology)
• Mice
• Mice, Inbred C57BL
• Nuclear Receptor Co-Repressor 2 (metabolism)
• Oncogene Proteins, Fusion (metabolism)
• Phosphorylation (drug effects)
• Phosphoserine (metabolism)
• Proteolysis (drug effects)
• Signal Transduction (drug effects)
• Survival Analysis
• Thionucleotides (pharmacology, therapeutic use)
• Translocation, Genetic (drug effects)
• Tretinoin (pharmacology, therapeutic use)