By using Myc-induced mouse model of lymphomagenesis and human B-cell lymphoma cell lines, we demonstrated that E6AP haploinsufficiency in mice or siRNA mediated inhibition of E6AP in human cells, is sufficient to restrain tumor development by inducing PML-dependent cellular senescence and preventing expansion of pre-leukemic B-cells. This evidence concerns the gene UBE3A and B-cell non-Hodgkin lymphoma.