The impact of trisomy 21 on early human hematopoiesis.

Although children with Down syndrome (DS) are not cancer-prone in general, they have a 150-fold increased risk of acute myeloid leukemia of DS (ML-DS) and a 33-fold increased risk of B-cell acute lymphoblastic leukemia (B-ALL). In virtually all cases of ML-DS, but not in other leukemias, the leukemic cells acquire N-terminal mutations in the GATA1gene, a key hematopoietic transcription factor and have an erythro-megakaryoblastic phenotype. The same N-terminal GATA1mutations are present in the clonally related, neonatal preleukemic disorder transient abnormal myelopoiesis (TAM), which is unique to DS and often precedes ML-DS.2 The identification of GATA1 mutations in ML-DS and TAM, and their unique association with DS and trisomy 21 (T21) (GATA1 mutations are not leukemogenic in the absence of T21), has provided an exciting and potentially tractable model of human myeloid leukemogenesis and, more generally, the impact of aneuploidy on human hematopoiesis