Multifactorial pathogenesis of childhood ALL. The development of childhood ALL is influenced by a combination of germline genetics, environmental factors (possibly associated with infection), and the chance occurrence of somatic mutations. DS is a major risk factor. The most significant allelic germline variants associated with ALL in children with and without DS are listed in the figure. Two of them (CDKN2A and IKZF1) are often also subjected to somatic loss-of-function mutations within the leukemic cells.