NOTCH1, SF3B1, and BIRC3 lesions provide: I) new insights on the mechanisms of leukemogenesis, tumor progression and chemoresistance in this leukemia; II) new biomarkers for the identification of poor risk patients, having individually shown correlations with survival in CLL; and III) new therapeutic targets, especially in the setting of high risk disease. Here, NOTCH1 is linked to B-cell chronic lymphocytic leukemia.