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.

【解说】

急性早幼粒细胞白血病（APL）即AML-M3型白血病，占急性非淋巴细胞白血病的10-25%。绝大多数APL病人具有特征性的非随机染色体t(15:17)，该易位使15号染色体上的早幼粒细胞白血病（PML）基因与位于17号染色体上的维甲酸受体α（RARα）基因融合，表达PML－RARα融合蛋白，病人对全反式维甲酸（ATRA）治疗敏感。

在变异型t(11;17)(q23;q21)APL患者的t(11:17)(q23;q21)中，11号染色体上的早幼粒细胞白血病锌指（PLZF）基因与位于17号染色体上的RARα基因融合，这些患者体内同时表达PLZF－RARα和RARα－PLZF两种融合蛋白。变异型t(11;17)(q23;q21)APL对ATRA不敏感，因此预后差。

采用8-CPT-cAMP结合ATRA的联合治疗策略，在携带PLZF/RARα和RARα/PLZF两种融合基因的小鼠白血病模型中发现，8-CPT-cAMP可增强ATRA诱导的幼稚白血病细胞分化及基因反式激活。8-CPT-cAMP结合ATRA，可以激活蛋白激酶A（PKA），引起PLZF/RARα中丝氨酸765位点的磷酸化，促进维甲酸和甲状腺激素受体沉默因子/受体辅阻遏子与PLZF/RARα分离，这可导致白血病细胞中局部染色质改变以及维甲酸信号通路激活。

此外，8-CPT-cAMP还促进ATRA对丝氨酸765位点的磷酸化诱导PLZF/RARα降解。在t(11;17)APL小鼠模型治疗试验中，他们证实8-CPT-cAMP可显著提高ATRA治疗效应，并能靶向抑制白血病起始细胞（leukemia-initiating cell）活性。因此，8-CPT-cAMP结合ATRA后通过诱导分化和癌蛋白降解来发挥治疗效应。