The PTEN and INK4A/ARF tumor suppressors maintain myelolymphoid homeostasis and cooperate to constrain histiocytic sarcoma development in humans
The PTEN and INK4A/ARF tumor suppressors maintain myelolymphoid homeostasis and cooperate to constrain histiocytic sarcoma development in humans
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DOI：
10.1016/j.ccr.2006.03.028
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发表时间：
2006-05-01
期刊：
影响因子：
50.3
通讯作者：
DePinho, Ronald A.
中科院分区：
文献类型：
--
作者：
Carrasco, Daniel R.;Fenton, Tim;DePinho, Ronald A.
组织细胞肉瘤（HS）是一种罕见的恶性增生的组织细胞的不确定的分子发病机制。在这里，Pten和Ink 4a/Arf肿瘤抑制因子在小鼠中的同时丢失的遗传分析揭示了由双表型髓淋巴样细胞的癌前扩增随后由HS的发展主导的肿瘤表型。Pten蛋白丢失仅发生在肿瘤的组织细胞部分，表明在HS的产生中逐步的遗传失活。类似地，人类HS显示出PTEN、p16（INK 4A）和p14（ARF）的遗传或表观遗传失活，支持这种遗传工程小鼠HS模型的相关性。这些遗传和翻译观察建立了Pten和Ink 4a/Arf在HS发展中的合作作用，并为人类HS的发病机制提供了机制见解。
Histiocytic sarcoma (HS) is a rare malignant proliferation of histiocytes of uncertain molecular pathogenesis. Here, genetic analysis of coincident loss of Pten and Ink4a/Arf tumor suppressors in the mouse revealed a neoplastic phenotype dominated by a premalignant expansion of biphenotypic myelolymphoid cells followed by the development of HS. Pten protein loss occurred only in the histiocytic portion of tumors, suggesting a stepwise genetic inactivation in the generation of HS. Similarly, human HS showed genetic or epigenetic inactivation of PTEN, p16(INK4A), and p14(ARF), supporting the relevance of this genetically engineered mouse model of HS. These genetic and translational observations establish a cooperative role of Pten and Ink4a/Arf in the development of HS and provide mechanistic insights into the pathogenesis of human HS.