Hypotheses to explain the pathogenesis of ALL in DS. (A) Constitutional trisomy 21 may enhance proliferation or survival of preleukemic lymphoid progenitors. An additional specific genetic event, such as a JAK2 mutation or additional chromosome X, cooperates with trisomy 21 to induce leukemia. This model is similar to the cooperation with GATA1 mutations in DS myeloid disorders. (B) The unique microenvironment in children with DS, caused by the presence of trisomy 21 in all body cells, results in an increased risk for usual childhood leukemogenic genetic events, such as TEL/AML1 and hyperdiploidy, and an increase in the common subtypes of childhood ALL. These 2 hypotheses are not mutually exclusive. Note that the latter model is speculative, but is presented as a hypothetical possibility to stimulate discussion and research in this area.