Although NOTCH1 mutations have a prominent role in the pathogenesis of CLL, alternative nonmutational mechanisms of NOTCH1 activation have been recently described in CLL [10], indicating that the constitutive activation of the pathway in this leukemia is more frequent than it was first estimated by the incidence of the main recurrent genetic lesions. The gene discussed is NOTCH1; the disease is B-cell chronic lymphocytic leukemia.