The discovery of NOTCH1 activation in CLL-HSCs and the presence of deregulated pre-BCR signaling driven by BRAF and EGR2 mutations in early CLL hematopoietic progenitors (122) led us to hypothesize that NOTCH1 alterations might cooperate with aberrant pre-BCR signals to favor the occurrence of the premalignant mature B clones. The gene discussed is NOTCH1; the disease is B-cell chronic lymphocytic leukemia.