Modeling the Initiation and Progression of Down Syndrome Associated Leukemia Using CRISPR/Cas9 at Single Cell Resolution
Leukemia is the most common cancer in children, accounting for almost 1 out of 3 cancers. This is also true in children with Down syndrome, a chromosomal abnormality caused by a third copy of chromosome 21. In particular, children with Down syndrome have a 150-fold increased risk of developing acute myeloid leukemia during the first years of their childhood. In fact, the first mutation occurs in the gene GATA1 during the development of the fetus at pregnancy. In 30% of newborns with Down syndrome a transient pre-leukemia disease occurs, which is characterized by an abnormal growth of immature cells carrying the GATA1 mutation, but resolves spontaneously in most patients. However, in 20% of these cases, the pre-leukemic disease later returns and progresses into full acute myeloid leukemia, which then carries additional mutations in other genes besides GATA1.
The overall aim of the proposal is to understand why an extra copy of chromosome 21 predisposes Down syndrome children to leukemia and to understand the mechanism of leukemia initiation and progression. For this, we are proposing to use CRISPR/Cas9 technology in human primary stem cells to model the leukemic disease in mice by introducing the same mutations observed in leukemic patients such as in GATA1 and other genes. This approach will be utilized to identify novel therapeutic targets against Down syndrome acute myeloid leukemia. Our long-term vision is to ultimately prevent the progression of transient pre-leukemia to acute myeloid leukemia by specifically targeting and removing the transient pre-leukemic cells.