GSE126300
PAX5 belongs to a functional transcription factor network commonly targeted in B-lineage leukemia
One of the most frequently mutated proteins in human B-lineage leukemia is the transcription factor PAX5 mutated in about one third of all cases. While reduced function of PAX5 has a clear link to human malignancy there is limited evidence for that the this directly impact the development of function of B-cell progenitors. One possible explanation to this comes from the finding that PAX5 mutated B-ALL display complex karyotypes and additional mutations. This suggestsindicating that PAX5 might be one component of a larger transcription factor network targeted in B-ALL. To investigate the functional network associated with PAX5 we identified proteins associated with this transcription factor using BioID technology. This identified more than 239 proteins several of which could be found mutated in human B-ALL. Most prominently we identified IKZF1, commonly mutated, and RUNX1, involved in the formation of ETV6-AML1 fusion protein formation, among the interaction partners. CHIPChIP-seq as well as PLAC-seq analysis supported the idea that these factors share regulatory elements in human B-ALL cells. Gene expression and mutation analysis of both mouse models and primary human leukemia suggested that these factors form a functional gene regulatory network targeted by multiple mutations in human B-ALL. In summary, we here present a model where a transcription factor can work through redeployment of other factors and not only through sites that it binds itself. Overall design: ChIP-Seq, ATAC-seq, and PLAC-sequencing in NALM6 B-ALL cells