Down-regulation of TCF8 is involved in the leukemogenesis of adult T-cell leukemia/lymphoma
Down-regulation of TCF8 is involved in the leukemogenesis of adult T-cell leukemia/lymphoma
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DOI：
10.1182/blood-2008-01-131185
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发表时间：
2008-07-15
期刊：
影响因子：
20.3
通讯作者：
Morishita, Kazuhiro
中科院分区：
文献类型：
--
作者：
Hidaka, Tomonori;Nakahata, Shingo;Morishita, Kazuhiro
成人t细胞白血病/淋巴瘤（ATLL）是由潜伏的人嗜t淋巴病毒-1 （HTLV-1）感染引起的。为了阐明病毒感染后白血病发生的分子机制，我们通过谱核分型精确定位了61例ATLL病例的605个染色体断点，并鉴定了10p11、14q11和14q32中常见的染色体断点。单核苷酸多态性（SNP）阵列-比较基因组杂交（CGH）、遗传和表达分析显示，在ATLL细胞中，转录因子8 （TCF8）经常被几种机制破坏，主要包括表观遗传失调。TCF8突变小鼠体内经常在胸腺或腹水中发生侵袭性CD4(+) t细胞淋巴瘤。体外ATLL细胞中TCF8表达下调与ATLL细胞对转化生长因子β 1 （tgf - β 1）的抗性有关，tgf - β 1是ATLL细胞的一个众所周知的特征，这表明摆脱tgf - β 1介导的生长抑制在ATLL的发病机制中很重要。这些发现表明TCF8在ATLL中具有肿瘤抑制作用。
Adult T-cell leukemia/lymphoma (ATLL) is caused by latent human T-lymphotropic virus-1 (HTLV-1) infection. To clarify the molecular mechanism underlying leukemogenesis after viral infection, we precisely mapped 605 chromosomal breakpoints in 61 ATLL cases by spectral karyotyping and identified frequent chromosomal breakpoints in 10p11, 14q11, and 14q32. Single nucleotide polymorphism (SNP) array-comparative genomic hybridization (CGH), genetic, and expression anallyses of the genes mapped within a common breakpoint cluster region in 10p11.2 revealed that in ATLL cells, transcription factor 8 (TCF8) was frequently disrupted by several mechanisms, including mainly epigenetic dysregulation. TCF8 mutant mice frequently developed invasive CD4(+) T-cell lymphomas in the thymus or in ascitic fluid in vivo. Downregulation of TCF8 expression in ATLL cells in vitro was associated with resistance to transforming growth factor beta 1 (TGF-beta 1), a well-known characteristic of ATLL cells, suggesting that escape from TGF-beta 1-mediated growth inhibition is important in the pathogenesis of ATLL. These findings indicate that TCF8 has a tumor suppressor role in ATLL.