The TLX1 oncogene drives aneuploidy in T cell transformation.
The TLX1 oncogene drives aneuploidy in T cell transformation.
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作者：
转录因子TLX 1在T细胞急性淋巴细胞白血病（T-ALL）的发病机制中起重要作用。然而，TLX 1下游T细胞转化的具体机制仍有待阐明。在这里，我们表明，强制表达的TLX 1在转基因小鼠诱导T-ALL肿瘤与频繁的缺失和突变的BCL 11b，并确定复发性突变和缺失的BCL 11B在16%的人类T-ALL的存在。最值得注意的是，小鼠TLX 1肿瘤通常是非整倍体，并显示出有丝分裂检查点激活的明显缺陷。机制上，TLX 1直接下调CHEK 1和其他有丝分裂控制基因的表达，并诱导非转化白血病前胸腺细胞中有丝分裂检查点的丢失。这些结果确定了一种新的机制，有助于染色体的错误分离和非整倍体活性在肿瘤发展的最早阶段，在癌症的发病机制。
The TLX1 transcription factor oncogene plays an important role in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL). However, the specific mechanisms of T-cell transformation downstream of TLX1 remain to be elucidated. Here we show that forced expression of TLX1 in transgenic mice induces T-ALL tumors with frequent deletions and mutations in Bcl11b, and identify the presence of recurrent mutations and deletions in BCL11B in 16% of human T-ALLs. Most notably, mouse TLX1 tumors were typically aneuploid and showed a marked defect in the activation of the mitotic checkpoint. Mechanistically, TLX1 directly downregulates the expression of CHEK1 and additional mitotic control genes and induces loss of the mitotic checkpoint in non transformed preleukemic thymocytes. These results identify a novel mechanism contributing to chromosomal missegregation and aneuploidy active at the earliest stages of tumor development in the pathogenesis of cancer.
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DOI：
10.1073/pnas.011404098
发表时间：
2001-01-02
影响因子：
11.1
作者：
Li, C;Wong, WH
通讯作者：
Wong, WH
影响因子：
64.8
作者：
Mullighan, Charles G.;Goorha, Salil;Downing, James R.
通讯作者：
Downing, James R.
DOI：
10.1016/j.bbrc.2007.02.003
发表时间：
2007-04-06
影响因子：
3.1
作者：
Kamimura, Kenya;Ohi, Hiroyuki;Kominami, Ryo
通讯作者：
Kominami, Ryo
影响因子：
11.4
作者：
Berger, R;Dastugue, N;Bernard, OA
通讯作者：
Bernard, OA
DOI：
10.1073/pnas.0806445106
发表时间：
2009-01-06
影响因子：
11.1
作者：
Margolin, Adam A.;Palomero, Teresa;Stolovitzky, Gustavo
通讯作者：
Stolovitzky, Gustavo