8-CPT-cAMP/all-trans retinoic acid targets t(11;17) acute promyelocytic leukemia through enhanced cell differentiation and PLZF/RARα degradation
8-CPT-cAMP/all-trans retinoic acid targets t(11;17) acute promyelocytic leukemia through enhanced cell differentiation and PLZF/RARα degradation
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DOI：
10.1073/pnas.1222863110
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发表时间：
2013-02-26
影响因子：
11.1
通讯作者：
Chen, Sai-Juan
中科院分区：
文献类型：
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作者：
Jiao, Bo;Ren, Zhi-Hong;Chen, Sai-Juan
急性早幼粒细胞白血病（APL）伴t（11;17）（q23;q21）对全反式维甲酸（ATRA）治疗的难治性引起临床医生和基础研究人员的关注。通过使用同时携带早幼粒细胞白血病锌指/维甲酸受体-α（PLZF/RAR α）和RAR α/PLZF融合基因的小鼠白血病模型，我们发现8-氯苯硫基腺苷-3 '，5'-环一磷酸（8-CPT-cAMP）增强细胞分化并改善ATRA在白血病母细胞中的基因反式激活。在机制上，与ATRA组合，8-CPT-cAMP激活PKA，引起PLZF/RAR α在Ser 765处的磷酸化，并导致维甲酸和甲状腺激素受体/核受体辅阻遏物的沉默介体从PLZF/RAR α的解离增加。该过程导致白血病细胞中局部染色质的改变和视黄酸通路的转录再激活。同时，8-CPT-cAMP也通过其Ser 765磷酸化增强ATRA诱导的PLZF/RAR α降解。在体内治疗t（11;17）APL小鼠模型表明，8-CPT-cAMP可通过靶向白血病起始细胞活性显著提高ATRA的治疗效果。这种诱导分化增强和癌蛋白降解的联合治疗可能对t（11;17）APL患者有益。
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-alpha (PLZF/RAR alpha) and RAR alpha/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/RAR alpha at Ser765 and resulting in increased dissociation of the silencing mediator for retinoic acid and thyroid hormone receptors/nuclear receptor corepressor from PLZF/RAR alpha. 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/RAR alpha 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.