By comparing the genomes of progenitor cells and mature cells of lymphoid and myeloid lineages in patients with chronic lymphocytic leukemia (CLL), Damm and colleagues confirmed that CLL originates from preleukemic CD34(+) progenitor cells and identified early CLL mutations that are associated with these progenitor cells. Moreover, they discovered that deregulation of B-cell receptor signaling may be one of the hallmarks of CLL, particularly in tumors with EGR2 mutations.