Down with leukemia Down syndrome is a congenital disorder caused by the trisomy of chromosome 21, and it is associated with a greatly increased risk of leukemia with origins in fetal development. Infants with Down syndrome are often born with a preleukemic condition, which later resolves in most cases. By using gene-edited human cells implanted into mouse models, Wagenblast et al. recapitulated the development of preleukemia and leukemia in the context of Down syndrome (see the Perspective by Roberts and Vyas). A specific mutation triggered a preleukemic condition in the context of trisomy 21 as expected, but progression to full-blown leukemia required a different genetic path and was not dependent on trisomy 21. Science , abf6202, this issue p. eabf6202 ; see also abj3957, p. 155