Whereas m-CLL clones exhibit more restricted autoreactivity (9, 40), the majority of um-CLL clones express low-affinity BCRs that are polyreactive recognizing self-antigens such as DNA, insulin and the cytoskeletal proteins myosin and vimentin, as well as foreign antigens such as bacterial DNA and lipopolysaccharides in addition to a spectrum of molecular motifs exposed on apoptotic cells (40, 52–57). Here, INS is linked to B-cell chronic lymphocytic leukemia.