Leukemia is often thought to arise due to multiple lesions, or ‘hits’, including (1) loss of genes that mediate hematopoietic differentiation and (2) mutations that confer proliferative and/or survival advantages.28 Our observations suggest that loss of Ebf1 genes is unlikely to be a primary driver of leukemogenesis by itself, but can synergize with mutations in other genes that increase the survival and relative fitness of leukemic cells. The gene discussed is EBF1; the disease is leukemia.