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Modeling the Initiation and Progression of Down Syndrome Associated Leukemia using CRISPR/Cas9 at Single Cell Resolution

Elvin Wagenblast

Elvin Wagenblast


University Health Network

Project Term: April 1, 2021 - March 31, 2023

Children with Down syndrome (Trisomy 21) have an increased risk of childhood leukemia and, in these cases, the initiating genetic alterations already occur during the development of the fetus. In 30% of newborns with Down syndrome, a pre-leukemia disease occurs, which in some cases can progress to acute myeloid leukemia. I am planning to determine why children with Down syndrome have an increased risk of developing leukemia with the goal to identify potential therapeutic targets.

Lay Abstract

Leukemia is the most common cancer in children, accounting for almost 1 out of 3 cancers. It is even more prevalent 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 30% of newborns with Down syndrome a transient pre-leukemia disease occurs, which is characterized by an abnormal growth of immature cells carrying mutations in the gene GATA1. In fact, in these cases, GATA1 mutations already occur during the development of the fetus at pregnancy. During the transient pre-leukemia phase, immature white blood cells called megakaryoblasts divide uncontrollably and can cause damage to several tissues, but in most patients it resolves spontaneously. 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 the already present GATA1 mutation. 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 blood stem cells to model the leukemic disease by introducing the same mutations observed in leukemic patients such as in GATA1 and other genes. These engineered human blood stem cells are then transplanted into mice in order to study their effect on blood and leukemia development. By introducing mutations of GATA1 into blood stem cells collected from healthy children with Down syndrome, we will be able to model the transient pre-leukemia phase in mice. Likewise, to model the progression to full acute myeloid leukemia, we are introducing a second mutation in the gene STAG2, which is one of the most frequently mutated genes in acute myeloid leukemia. With this model in hand, we will be able to assess which gene pathways are affected in Down syndrome pre-leukemia and acute myeloid leukemia in order to identify novel therapeutic targets that could eliminate the cancerous cells. Our long-term vision is to prevent the progression of transient pre-leukemia to acute myeloid leukemia by specifically removing the transient pre-leukemic cells. This could serve as a general prevention strategy in Down syndrome children diagnosed with pre-leukemia.

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