Burkitt lymphoma (BL) is an aggressive B-cell lymphoma characterized by translocation and deregulation of the proto-oncogene c-MYC. Transcription factor 3 (TCF3) has also been shown to be involved in BL pathogenesis. In BL, TCF3 is constitutively active, and/or expression of its transcriptional targets are altered as a result of BL-associated mutations. Here, we found that BL-related TCF3 mutations affect TCF3 alternative splicing, in part by reducing binding of the splicing regulator hnRNPH1 to exon 18b. This leads to greater exon 18b inclusion, thereby generating more of the mutated E47 isoform of TCF3. Interestingly, upregulation of E47 dysregulates the expression of TCF3 targets PTPN6, and perhaps CCND3, which are known to be involved in BL pathogenesis. Our findings thus reveal a mechanism by which TCF3 somatic mutations affect multilayered gene regulation underlying BL pathogenesis.

Burkitt淋巴瘤（BL）是一种侵袭性B细胞淋巴瘤，其特征在于原癌基因c-MYC易位和失调。转录因子3（TCF3）也已被证明参与BL发病机理。在BL中，TCF3具有组成型活性，和/或由于BL相关突变而改变了其转录靶标的表达。在这里，我们发现与BL相关的TCF3突变会影响TCF3选择性剪接，部分是通过减少剪接调节子hnRNPH1与外显子18b的结合来实现的。这导致更大的外显子18b包含，从而产生更多的TCF3的突变的E47同工型。有趣的是，E47的上调会异常调节TCF3靶标PTPN6和CCND3的表达，已知与BL发病机理有关。因此，我们的发现揭示了TCF3体细胞突变影响BL发病机理的多层基因调控机制。