Department of Internal Medicine, American University of Beirut, Beirut, Lebanon.
Int J Hematol. 2010 Jun;91(5):742-7. doi: 10.1007/s12185-010-0582-0. Epub 2010 May 11.
Acute promyelocytic leukemia (APL) is characterized by a t(15;17) translocation that yields a PML/RARA fusion protein. Expression of PML/RARA, a potent transcriptional repressor, induces APL in mice. Both retinoic acid (RA) and arsenic trioxide directly target PML/RARA-mediated transcriptional repression and protein stability, inducing rapid differentiation of the promyelocytes and clinical remission in most APL patients. RA also triggers growth arrest and progressive clearance of leukemia initiating cells (LIC), both ex vivo and in vivo. Suboptimal RA concentrations or expression of the PLZF/RARA variant allows complete RA-induced differentiation, but neither LIC clearance nor disease remission. Thus, RA-induced differentiation and LIC clearance may be uncoupled. The RA/arsenic trioxide association, which dramatically synergizes for PML/RARA degradation but not for differentiation, rapidly clears LIC in a proteasome-dependent manner, resulting in APL eradication in murine models and patients. Collectively, these results demonstrate that LIC clearance, which mirrors PML/RARA degradation, is the primary basis for APL cure by the RA/arsenic trioxide association, rather than differentiation. Oncogene degradation could be a generally applicable therapeutic strategy to clear LICs in several types of tumors.
急性早幼粒细胞白血病（APL）的特征是存在 t（15;17）易位，导致产生 PML/RARA 融合蛋白。PML/RARA 的表达，一种有效的转录抑制剂，可在小鼠中诱导 APL。全反式维甲酸（RA）和三氧化二砷均可直接靶向 PML/RARA 介导的转录抑制和蛋白稳定性，从而迅速诱导早幼粒细胞分化，并使大多数 APL 患者临床缓解。RA 还会引发细胞生长停滞和白血病起始细胞（LIC）的逐渐清除，无论是在体外还是体内。RA 浓度不理想或 PLZF/RARA 变体的表达可使完全的 RA 诱导分化，但不会清除 LIC 或缓解疾病。因此，RA 诱导分化和 LIC 清除可能是脱偶联的。RA/三氧化二砷联合使用可显著增强 PML/RARA 的降解，但对分化没有影响，它可迅速通过蛋白酶体依赖性方式清除 LIC，从而在小鼠模型和患者中根除 APL。综上所述，这些结果表明，与 PML/RARA 降解相吻合的 LIC 清除是 RA/三氧化二砷联合治疗 APL 治愈的主要基础，而不是分化。癌基因降解可能是一种通用的治疗策略，可用于清除多种肿瘤类型中的 LIC。
