Disruption of the PHRF1 Tumor Suppressor Network by PML-RARα Drives Acute Promyelocytic Leukemia Pathogenesis.
Disruption of the PHRF1 Tumor Suppressor Network by PML-RARα Drives Acute Promyelocytic Leukemia Pathogenesis.
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DOI：
10.1016/j.celrep.2015.01.024
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发表时间：
2015-02-17
期刊：
影响因子：
8.8
通讯作者：
Atfi A
中科院分区：
文献类型：
--
作者：
Prunier C;Zhang MZ;Kumar S;Levy L;Ferrigno O;Tzivion G;Atfi A
PHRF1通过触发同源结构域转录因子TGF的降解，作为TGF-β肿瘤抑制通路的重要组成部分。这导致cPML重新分布到细胞质中，在那里它通过TGF-β受体协调Smad2的磷酸化和激活。在急性早幼粒细胞白血病（APL）中，已知PML-RARα的获得会阻碍TGF-β信号传导的关键方面，包括髓细胞分化。尽管这些缺陷被认为依赖于cPML活性的抑制，但这种现象的机制仍然是谜。在这里，我们发现PML-RARα的一个异常功能是干扰TGIF的分解，可能是通过与PHRF1竞争结合TGIF，最终导致cPML的隔离和失活。强化PHRF1活性足以恢复人胚细胞中TGF-β细胞抑制剂信号，并抑制APL小鼠模型中的APL形成，这为PML-RARα抑制PHRF1活性是APL发病机制的关键决定因素提供了概念验证数据。
PHRF1 functions as an essential component of the TGF-β tumor suppressor pathway by triggering degradation of the homeodomain transcription factor TGIF. This leads to redistribution of cPML into the cytoplasm, where it coordinates phosphorylation and activation of Smad2 by the TGF-β receptor. In acute promyelocytic leukemia (APL), acquisition of PML-RARα is known to impede critical aspects of TGF-β signaling, including myeloid differentiation. Although these defects are thought to rely on suppression of cPML activity, the mechanisms underlying this phenomenon remain enigmatic. Here, we find that an abnormal function of PML-RARα is to interfere with TGIF breakdown, presumably by competing with PHRF1 for binding to TGIF, culminating in cPML sequestration and inactivation. Enforcing PHRF1 activity is sufficient to restore TGF-β cytostatic signaling in human blasts and suppress APL formation in a mouse model of APL, providing proof-of-concept data that suppression of PHRF1 activity by PML-RARα represents a critical determinant in APL pathogenesis.