Here, it is demonstrated that early B-cell progenitors express 2',3'-cyclic-nucleotide 3' phosphodiesterase (CNP) and that when targeted with <i>Sleeping Beauty</i> (<i>SB</i>) mutagenesis, <i>Trp53<sup>R270H</sup></i> mutation or <i>Pten</i> loss gave rise to highly penetrant lymphoid diseases, predominantly follicular lymphoma and DLBCL.