Telomerase targeting by retinoids in cells from patients with myeloid leukemias of various subtypes, not only APL
Telomerase targeting by retinoids in cells from patients with myeloid leukemias of various subtypes, not only APL
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DOI：
10.1038/sj.leu.2404127
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发表时间：
2006-04-01
期刊：
影响因子：
11.4
通讯作者：
Ségal-Bendirdjian, E
中科院分区：
文献类型：
--
作者：
Pendino, F;Hillion, J;Ségal-Bendirdjian, E
人们提出了多种特异性抑制端粒酶（人端粒酶逆转录酶（hTERT））的策略，但迄今为止只有少数策略与抗癌治疗具有临床相关性。最近，我们发现，长期使用全反式视黄酸（ATRA）（一种临床批准用于急性早幼粒细胞白血病（APL）分化治疗的化合物）可抑制分化抗性 APL 细胞系中的 hTERT，导致端粒缩短和死亡。该信号传导需要视黄酸受体 α (RAR α) 和视黄酸 X 受体 (RXR) 的共同激活。与仅在这种白血病亚型中成功的分化疗法相反，端粒酶靶向途径也可用于非 APL。在这里，我们证明了 hTERT 的抑制发生在来自离体暴露于 ATRA 或合成类维生素A的各种亚型骨髓性白血病患者的新鲜母细胞中。这些结果支持这样的观点，即通过 hTERT 靶向，类视黄醇可以诱导端粒缩短和细胞死亡，并且应考虑将其整合到难以成熟的骨髓性白血病的治疗方案中。
Numerous strategies have been proposed to specifically inhibit telomerase (human telomerase reverse transcriptase (hTERT)) but to date only a few are clinically relevant in anticancer therapy. Recently, we have shown that long-term treatment with all-trans retinoic acid (ATRA), a compound clinically approved for differentiation therapy of acute promyelocytic leukemia (APL), represses hTERT in differentiation-resistant APL cell lines leading to telomere shortening and death. This signaling requires the co-activation of the retinoic acid receptor alpha (RAR alpha) and the retinoic X receptor (RXR). In contrast to differentiation-therapy, which is only successful in this subtype of leukemia, the telomerase-targeted pathway could also be of use in non-APL. Here, we demonstrate that repression of hTERT occurs in fresh blasts cells from patients with myeloid leukemias of various subtypes exposed ex vivo to ATRA or synthetic retinoids. These results support the idea that, by hTERT targeting, retinoids can induce telomere shortening and cell death and their integration in therapy protocols for myeloid leukemias refractory to maturation should be considered.