Altucci Lucia, Rossin Aurélie, Hirsch Oliver, Nebbioso Angela, Vitoux Dominique, Wilhelm Emmanuelle, Guidez Fabien, De Simone Mariacarla, Schiavone Ettore Mariano, Grimwade David, Zelent Arthur, de Thé Hugues, Gronemeyer Hinrich
Department of Cell Biology and Signal Transduction, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch Cedex, C.U. de Strasbourg, France.
Cancer Res. 2005 Oct 1;65(19):8754-65. doi: 10.1158/0008-5472.CAN-04-3569.
Apart from PML-retinoic acid receptor-alpha (RARalpha) acute promyelocytic leukemia all other acute myeloid leukemias (AML) are unresponsive to retinoid differentiation therapy. However, elevating the levels of cyclic AMP (cAMP) confers onto retinoid X receptor (RXR)-selective agonists ("rexinoids") the ability to induce terminal granulocyte differentiation and apoptosis of all-trans retinoic acid-resistant and insensitive AML cells and patients' blasts. Protein kinase A activation leads to corepressor release from the RAR subunit of the RAR-RXR heterodimer, resulting in "desubordination" of otherwise silent RXR, which acquires transcriptional competence in response to cognate ligands. Rexinoid-cAMP induction of endogenous RARbeta is blunted in mouse embryo fibroblasts lacking RARs, but reintroduction of exogenous RARalpha reestablishes responsiveness, thus confirming that the RARalpha-RXR heterodimer is the rexinoid mediator. The apoptogenic effect of this treatment involves enhanced expression of the death receptor DR5 and its cognate ligand, tumor necrosis factor-related apoptosis inducing ligand, both of which are known to induce apoptosis in a tumor cell-selective manner and lead to the activation of initiator caspases. Immunohistochemistry confirmed induction of tumor necrosis factor-related apoptosis inducing ligand and DR5 in AML patient blasts cultured ex vivo. AML patients' blasts responded to rexinoid-cAMP combination treatment with induction of maturation and apoptosis, independent of karyotype, immunophenotype, and French-American-British classification status. Clonogenic assays revealed complete inhibition of blast clonogenicity in four out of five tested samples. Our results suggest that despite the genetic, morphologic, and clinical variability of this disease, the combination of rexinoids and cAMP-elevating drugs, such as phosphodiesterase inhibitors, might lead to a novel therapeutic option for AML patients by inducing a tumor-selective death pathway.
除了早幼粒细胞白血病-维甲酸受体α（RARα）急性早幼粒细胞白血病外，所有其他急性髓系白血病（AML）对维甲酸分化疗法均无反应。然而，提高环磷酸腺苷（cAMP）水平可赋予维甲酸X受体（RXR）选择性激动剂（“类视黄醇”）诱导全反式维甲酸耐药和不敏感AML细胞及患者原始细胞终末粒细胞分化和凋亡的能力。蛋白激酶A激活导致共抑制因子从RAR-RXR异二聚体的RAR亚基释放，导致原本沉默的RXR“解除从属”，使其在响应同源配体时获得转录能力。在缺乏RAR的小鼠胚胎成纤维细胞中，类视黄醇-cAMP对内源性RARβ的诱导作用减弱，但重新引入外源性RARα可恢复反应性，从而证实RARα-RXR异二聚体是类视黄醇的介质。这种治疗的凋亡作用涉及死亡受体DR5及其同源配体肿瘤坏死因子相关凋亡诱导配体的表达增强，已知这两者均以肿瘤细胞选择性方式诱导凋亡并导致起始半胱天冬酶的激活。免疫组织化学证实了在体外培养的AML患者原始细胞中肿瘤坏死因子相关凋亡诱导配体和DR5的诱导。AML患者的原始细胞对类视黄醇-cAMP联合治疗有反应，可诱导成熟和凋亡，与核型、免疫表型和法美英分类状态无关。集落形成试验显示，在五个测试样本中有四个样本的原始细胞集落形成被完全抑制。我们的结果表明，尽管该疾病存在遗传、形态和临床变异性，但类视黄醇与升高cAMP药物（如磷酸二酯酶抑制剂）的联合应用可能通过诱导肿瘤选择性死亡途径为AML患者带来一种新的治疗选择。
