Characterization of the genome-wide TLX1 binding profile in T-cell acute lymphoblastic leukemia
Characterization of the genome-wide TLX1 binding profile in T-cell acute lymphoblastic leukemia
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DOI：
10.1038/leu.2015.162
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发表时间：
2015-12-01
期刊：
影响因子：
11.4
通讯作者：
Van Vlierberghe, P.
中科院分区：
文献类型：
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作者：
Durinck, K.;Van Loocke, W.;Van Vlierberghe, P.
TLX1转录因子在T细胞急性淋巴细胞白血病(T-ALL)的多步骤发病机制中起重要作用，在T细胞恶性转化过程中经常与NOTCH1激活协同作用。然而，这些T细胞特异性癌基因在转化过程中相互协作的确切分子机制仍有待建立。在这里，我们使用染色质免疫沉淀和测序来建立人类T-ALL中TLX1的全基因组结合模式。这种整合的基因组学方法表明，异位TLX1的表达驱动了T细胞特异性增强子的抑制，并在包括IL7R和NOTCH3在内的关键靶基因上介导了与NOTCH1的意外转录拮抗。这些现象协调地触发了人胸腺前体细胞中TLX1驱动的白血病前表型，这让人想起在小鼠TLX1肿瘤模型中观察到的胸腺退化，并为获得激活的NOTCH1突变创造了强大的遗传压力，这是完全转化白血病的先决条件。总之，我们的结果揭示了在肿瘤发展的早期阶段协同癌基因之间的功能拮抗，并为TLX1驱动的人类白血病的多步骤发病机制提供了新的见解。
The TLX1 transcription factor is critically involved in the multi-step pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) and often cooperates with NOTCH1 activation during malignant T-cell transformation. However, the exact molecular mechanism by which these T-cell specific oncogenes cooperate during transformation remains to be established. Here, we used chromatin immunoprecipitation followed by sequencing to establish the genome-wide binding pattern of TLX1 in human T-ALL. This integrative genomics approach showed that ectopic TLX1 expression drives repression of T cell-specific enhancers and mediates an unexpected transcriptional antagonism with NOTCH1 at critical target genes, including IL7R and NOTCH3. These phenomena coordinately trigger a TLX1-driven pre-leukemic phenotype in human thymic precursor cells, reminiscent of the thymus regression observed in murine TLX1 tumor models, and create a strong genetic pressure for acquiring activating NOTCH1 mutations as a prerequisite for full leukemic transformation. In conclusion, our results uncover a functional antagonism between cooperative oncogenes during the earliest phases of tumor development and provide novel insights in the multi-step pathogenesis of TLX1-driven human leukemia.