Burkitt-lymphoma-related TCF3 mutations alter TCF3 alternative splicing by disrupting hnRNPH1 binding.

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/orexpression of its transcriptional targetsare alteredas 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 regulatorhnRNPH1 to exon 18b. This leads to greater exon 18b inclusion, thereby generating more of the mutated E47 isoform of TCF3. Interestingly, upregulationof E47 dysregulates expression of TCF3 targets PTPN6 , and perhaps CCND3 , whichareknown to be involved in BL pathogenesis. Our findings thus reveal a mechanismby which TCF3 somatic mutations affectmultilayered gene regulation underlying BL pathogenesis.