早幼粒细胞白血病-肿瘤蛋白 53 轴的激活是急性早幼粒细胞白血病治愈的基础。
Activation of a promyelocytic leukemia-tumor protein 53 axis underlies acute promyelocytic leukemia cure.
机构信息
1] Université Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis, Paris, France. [2] INSERM UMR 944, Equipe Labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Hôpital St. Louis, Paris, France. [3] CNRS UMR 7212, Hôpital St. Louis, Paris, France. [4].
1] Université Paris Diderot, Sorbonne Paris Cité, Hôpital St. Louis, Paris, France. [2] INSERM UMR 944, Equipe Labellisée par la Ligue Nationale contre le Cancer, Institut Universitaire d'Hématologie, Hôpital St. Louis, Paris, France. [3] CNRS UMR 7212, Hôpital St. Louis, Paris, France.
出版信息
Nat Med. 2014 Feb;20(2):167-74. doi: 10.1038/nm.3441. Epub 2014 Jan 12.
Acute promyelocytic leukemia (APL) is driven by the promyelocytic leukemia (PML)-retinoic acid receptor-α (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.
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-α（PML-RARA）融合蛋白驱动的，它干扰核受体信号和 PML 核体（NB）组装。APL 是唯一通过靶向治疗明确治愈的恶性肿瘤：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 降解。然而，治疗效果的细胞和分子决定因素仍存在争议。我们证明，在 APL 的小鼠模型中，功能性 Pml-转化相关蛋白 53（Trp53）轴是根除白血病起始细胞所必需的。在 RA 诱导的 PML-RARA 降解后，正常的 Pml 会引发 NB 的重新形成，并诱导 Trp53 反应，其具有衰老而不是凋亡的特征，最终消除 APL 起始活性。除了触发 PML-RARA 降解外，三氧化二砷还靶向正常的 Pml 以增强 NB 的重新形成，这可能解释了其在临床上的效力，无论是单独使用还是与 RA 联合使用。这种由治疗触发的 NB 恢复引发的 Pml-Trp53 检查点是 PML-RARA 驱动的 APL 所特有的，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 的生物发生是可靶向的，因此它可以在非 APL 恶性肿瘤中被治疗性利用。
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