Activation of a promyelocytic leukemia-tumor protein 53 axis underlies acute promyelocytic leukemia cure
Activation of a promyelocytic leukemia-tumor protein 53 axis underlies acute promyelocytic leukemia cure
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DOI：
10.1038/nm.3441
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发表时间：
2014-02-01
期刊：
影响因子：
82.9
通讯作者：
de The, Hugues
中科院分区：
文献类型：
--
作者：
Ablain, Julien;Rice, Kim;de The, Hugues
急性早幼粒细胞白血病(APL)是由早幼粒细胞白血病(PML)-维甲酸受体-a(PML-RARA)融合蛋白驱动的，该融合蛋白干扰核受体信号转导和PML核体(NB)组装。APL是唯一一种通过靶向治疗而最终治愈的恶性肿瘤：维甲酸(RA)和/或三氧化二砷，这两种药物都通过不重叠的途径触发PML-RARA的降解。然而，治疗效果的细胞和分子决定因素仍然存在争议。我们证明，在APL小鼠模型中，需要一个功能性的PML转化相关蛋白53(TrP53)轴来根除白血病启动细胞。在RA诱导的PML-RARA降解过程中，正常的PML诱导NB重塑，并诱导TrP53反应，呈现衰老而不是凋亡的特征，最终取消APL的启动活性。除了触发PML-RARA降解外，三氧化二砷还针对正常的PML促进NB重塑，这可能解释了其临床效力，单独或与RA。这个由治疗触发的NB修复启动的PML-Trp53检查点是针对PML-RARA驱动的APL的，但不是RA耐药的早幼粒细胞白血病锌指(PLZF)-RARA变体。然而，由于NB的生物生成是可药物的，它可以用于非APL恶性肿瘤的治疗。
Acute promyelocytic leukemia (APL) is driven by the promyelocytic leukemia (PML)-retinoic acid receptor-a (PML-RARA) fusion protein, which interferes with nuclear receptor signaling and PML nuclear body (NB) assembly. APL is the only malignancy definitively cured by targeted therapies: retinoic acid (RA) and/or arsenic trioxide, which both trigger PML-RARA degradation through nonoverlapping pathways. Yet, the cellular and molecular determinants of treatment efficacy remain disputed. We demonstrate that a functional Pml-transformation-related protein 53 (Trp53) axis is required to eradicate leukemia-initiating cells in a mouse model of APL. Upon RA-induced PML-RARA degradation, normal Pml elicits NB reformation and induces a Trp53 response exhibiting features of senescence but not apoptosis, ultimately abrogating APL-initiating activity. Apart from triggering PML-RARA degradation, arsenic trioxide also targets normal PML to enhance NB reformation, which may explain its clinical potency, alone or with RA. This Pml-Trp53 checkpoint initiated by therapy-triggered NB restoration is specific for PML-RARA-driven APL, but not the RA-resistant promyelocytic leukemia zinc finger (PLZF)-RARA variant. Yet, as NB biogenesis is druggable, it could be therapeutically exploited in non-APL malignancies.