Project Term
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Project Summary
Children with Down Syndrome (DS) have a 30-fold increased risk of B-cell Acute Lymphoblastic Leukemia (B-ALL). We aim to identify the cells of origin in DS-B-ALL and define its unique features. Using scRNA-seq, we will create an immune cell atlas to study how trisomy 21 (T21) affects lymphopoiesis, and map the cellular and molecular heterogeneity in DS-B-ALL at disease onset and during relapse. These studies will help understand the B lymphoid defects in T21 and how they predispose to DS-B-ALL.
Lay Abstract
Children with Down Syndrome (DS), caused by an extra copy of chromosome 21 (Trisomy 21, or T21), have an approximately 30 times higher risk of developing B-cell Acute Lymphoblastic Leukemia (B-ALL) compared to other children. This type of leukemia (DS-B-ALL) often involves changes in the CRLF2 gene and is linked to poorer outcomes. However, the specific cells that lead to DS-B-ALL remain unknown. Understanding these cells could enable targeted therapies and improve outcomes for affected children.
The goal of my research is to identify the cells that give rise to DS-B-ALL, and understand how these cells change when they transform to leukemia cells. We will first create immune cell map using human developmental tissues to assess how T21 alters B cell formation. Identifying vulnerable cell types that may be predisposed to leukemia will help us understand how DS-B-ALL begins. We will then study leukemia cells from Down Syndrome B-ALL patients to understand how the cells progress to leukemia, and what happens when the treatment does not work.
Our research is unique as we examine T21 B cell development across human developmental tissues and stages. Using advanced single-cell technologies, we can understand how the function of individual cells is altered. This allows us to identify early B cell progenitors in tissues where immune cells develop. We will dissect whether the affected immune cell progenitors are embryonic or adult type, as embryonic B cells progenitors have been linked to aggressive B-ALL forms.
Success indicators for this project include identifying specific disruptions in B cell development caused by T21, characterizing the cells that give rise to DS-B-ALL, and understanding how these cells change when leukemia develops. Finding cell types predisposed to blood cancer due to T21 would be a significant step in understanding and preventing the disease and developing better therapies.
This research could lead to future studies on targeted pathways disrupted in DS-B-ALL. While this research is in its early stages it has the potential to inform new therapies targeting DS-B-ALL’s specific vulnerabilities. By understanding how T21 affects B cell development and leukemia risk, we can create strategies for prevention and treatment, benefiting children with Down Syndrome facing the heightened risk for aggressive leukemia.
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