Somatic Recombination Between an Ancient and a Recent Gene Variant Is Associated with the NOTCH2 Gain-of-Function Phenotype in Chronic Lymphocytic Leukemia.

Constitutively active NOTCH2 signaling is a hallmark in chronic lymphocytic leukemia (CLL). The precise underlying defect remains obscure. Here we show that the mRNA sequence coding for the NOTCH2 negative regulatory region (NRR) is consistently deleted in CLL cells. The most common deletion is associated with two intronic single nucleotide variations (SNVs) which either create (CTTT, G>A for rs2453058) or destroy (CTCT, A>G for rs5025718) a putative splicing branch point sequence (BPS). Phylogenetic analysis demonstrates that rs2453058 is part of an ancient gene variant () which is associated with type 2 diabetes mellitus (T2DM) and is two times more frequent in Europeans than in East Asians, resembling the differences in CLL incidence. In contrast, rs5025718 belongs to a recent variant () that dominates the world outside Africa. Nanopore sequencing indicates that somatic reciprocal crossing over between rs2453058 () and rs5025718 () leads to recombined alleles with altered BPS patterns in CLL cases. This would explain the loss of the NRR domain by aberrant pre-mRNA splicing and consequently the NOTCH2 gain-of-function phenotype. Together, our findings suggest that somatic recombination of inherited variants might be relevant to CLL etiology and may at least partly explain its geographical clustering.