BCL2 promoter region mutations are an independent marker of BCL2 level in lymphoid malignancies

BCL2 upregulation is a key driver of lymphomagenesis and treatment response. By analyzing large-scale whole-genome datasets, we identify a lymphoma-specific noncoding mutational hotspot encompassing the BCL2 promoter that, independent of other factors such as the t(14;18) translocation, strongly associates with allele-specific BCL2 upregulation. These mutations disrupt regulatory protein-binding sites, alter BCL2 isoform balance, and associate with worse survival in diffuse large B-cell lymphoma.