LEF1 is a novel molecular player in CLL, with effects depending on protein levels and isoform switching. Specifically, IgHV-unmutated CLL cells are characterized by higher levels of LEF1 and by the presence of a shorter isoform. Together, these quantitative and qualitative changes induce differential binding to the DNA, triggering expression of proproliferation genes, at variance with IgHV-mutated CLL cells where the modulated pathways involve mostly prosurvival genes.