Modeling The Initiation And Evolution Of Down Syndrome Associated Leukemia Using Crispr/Cas9

Children with Down syndrome, also known as trisomy 21, have a significantly increased risk of childhood acute leukemia in the first few years after birth. The acute leukemia phase is preceded with a transient pre-leukemia phase in newborns, which is characterized by a clonal proliferation of immature megakaryocytes carrying somatic mutations in the GATA binding protein 1 (GATA1). These acquired GATA1 mutations lead to the expression of the GATA1 short isoform and prevent the expression of the GATA1 long isoform. The pre-leukemia undergoes spontaneous remission within the first few months after birth. In 20% - 30% of the cases, children progress to acute myeloid leukemia (AML) after remission, in which the pre-leukemic clone acquires additional mutations, such as in genes of the cohesin complex. It is hypothesized that this represents a multi-step process of leukemogenesis with three distinct genetic events: trisomy 21, GATA1 mutation and additional tertiary mutations.