The TCF-1 and LEF-1 transcription factors have cooperative and opposing roles in T cell development and malignancy.
The TCF-1 and LEF-1 transcription factors have cooperative and opposing roles in T cell development and malignancy.
复制标题
DOI：
10.1016/j.immuni.2012.08.009
复制
发表时间：
2012-11-16
期刊：
影响因子：
32.4
通讯作者：
Xue HH
中科院分区：
文献类型：
--
作者：
Yu S;Zhou X;Steinke FC;Liu C;Chen SC;Zagorodna O;Jing X;Yokota Y;Meyerholz DK;Mullighan CG;Knudson CM;Zhao DM;Xue HH
已知TCF-1和LEF-1转录因子在正常胸腺细胞发育中起关键作用。出乎意料的是，我们发现TCF-1缺陷（Tcf 7 −/−）小鼠发生了侵袭性T细胞恶性肿瘤，类似于人类T细胞急性淋巴细胞白血病（T-ALL）。令人惊讶的是，LEF-1在癌前Tcf 7 −/−早期胸腺细胞和淋巴瘤细胞中异常上调。我们进一步证明了TCF-1直接抑制了早期胸腺细胞中LEF-1的表达，并且Lef 1的条件性失活极大地延迟或预防了Tcf 7 −/−小鼠中的T细胞恶性肿瘤。在人类T-ALL中，早期胸腺祖细胞（ETP）亚型与TCF 7表达减少相关，其中2例ETP-ALL病例存在TCF 7基因缺失。我们还发现，TCF-1和LEF-1是T细胞系定型的关键，但它们是早期胸腺细胞成熟超过CD 4 − CD 8 −阶段所必需的。因此，TCF-1具有双重作用，即，与LEF-1协同作用以促进胸腺细胞成熟，同时抑制LEF-1表达以防止发育中的胸腺细胞的恶性转化。
The TCF-1 and LEF-1 transcription factors are known to play critical roles in normal thymocyte development. Unexpectedly, we found that TCF-1-deficient (Tcf7−/−) mice developed aggressive T-cell malignancy, resembling human T-cell acute lymphoblastic leukemia (T-ALL). Surprisingly, LEF-1 was aberrantly upregulated in pre-malignant Tcf7−/− early thymocytes and lymphoma cells. We further demonstrated that TCF-1 directly repressed LEF-1 expression in early thymocytes and that conditional inactivation of Lef1 greatly delayed or prevented T-cell malignancy in Tcf7−/− mice. In human T-ALLs, an early thymic progenitor (ETP) subtype was associated with diminished TCF7 expression, and two of the ETP-ALL cases harbored TCF7 gene deletions. We also showed that TCF-1 and LEF-1 were dispensable for T-lineage commitment but instead were required for early thymocytes to mature beyond the CD4−CD8− stage. TCF-1 thus has dual roles, i.e., acting cooperatively with LEF-1 to promote thymocyte maturation while restraining LEF-1 expression to prevent malignant transformation of developing thymocytes.
登录
查看更多内容
LEF-1的新作用，LEF-1是Wnt信号传导的中央转录介质，在白血病发生中。
影响因子：
15.3
作者：
Petropoulos, Konstantin;Arseni, Natalia;Schessl, Christina;Stadler, Christiane R.;Rawat, Vijay P. S.;Deshpande, Aniruddha J.;Heilmeier, Bernhard;Hiddemann, Wolfgang;Quintanilla-Martinez, Leticia;Bohlander, Stefan K.;Feuring-Buske, Michaela;Buskel, Christian
通讯作者：
Buskel, Christian
影响因子：
64.8
作者：
Mullighan, Charles G.;Goorha, Salil;Downing, James R.
通讯作者：
Downing, James R.
影响因子：
20.3
作者：
Morse, HC;Anver, MR;Ward, JM
通讯作者：
Ward, JM
DOI：
10.1073/pnas.1110230108
发表时间：
2011-12-13
影响因子：
11.1
作者：
Germar, Kristine;Dose, Marei;Gounari, Fotini
通讯作者：
Gounari, Fotini
影响因子：
20.3
作者：
Lin, YW;Nichols, RA;Aplan, PD
通讯作者：
Aplan, PD