Carrasco Daniel R, Fenton Tim, Sukhdeo Kumar, Protopopova Marina, Enos Miriam, You Mingjian J, Di Vizio Dolores, Nogueira Cristina, Stommel Jayne, Pinkus Geraldine S, Fletcher Christopher, Hornick Jason L, Cavenee Webster K, Furnari Frank B, Depinho Ronald A
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
Cancer Cell. 2006 May;9(5):379-90. doi: 10.1016/j.ccr.2006.03.028.
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.
组织细胞肉瘤（HS）是一种罕见的组织细胞恶性增殖性疾病，其分子发病机制尚不清楚。在此，对小鼠中Pten和Ink4a/Arf肿瘤抑制因子同时缺失的基因分析显示，一种肿瘤表型以双表型骨髓淋巴细胞的癌前扩增为主导，随后发展为HS。Pten蛋白缺失仅发生在肿瘤的组织细胞部分，提示在HS发生过程中存在逐步的基因失活。同样，人类HS显示PTEN、p16(INK4A)和p14(ARF)的基因或表观遗传失活，支持了这种HS基因工程小鼠模型的相关性。这些基因和转化研究结果确立了Pten和Ink4a/Arf在HS发生中的协同作用，并为人类HS的发病机制提供了机制性见解。
