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SPRING 2024
Research Advancements: Neurodevelopmental Disorders
Transforming Treatment Paradigms for Down Syndrome: Targeting Preleukemia Early
D
own syndrome, known medically as trisomy 21 (T21), affects approximately 1 in 700 newborns and is associated with a spectrum of health challenges, including a heightened risk of leukemia and liver diseases. Notably, around 30% of Down syndrome newborns develop a preleukemic condition known as transient abnormal myelopoiesis (TAM), which can evolve into acute myeloid leukemia. Addressing these conditions early could significantly alter outcomes for these vulnerable children.
Preliminary data from our research has revealed dramatic changes in blood cell production during fetal development in those with trisomy 21. We have observed an increased number of HSCs, yet these cells exhibit reduced self-renewal capacity and dysfunctional gene expression profiles. Notably, these HSCs demonstrate an inability to balance differentiation output towards B-cells and myeloid cells, exhibiting characteristics typically associated with aged HSCs. This early aging phenotype may contribute significantly to the development of hematological diseases and other complications in Down syndrome.
Our research project is focused to unravel the cellular and molecular mechanisms underpinning the onset of preleukemia in children with Collaboration is at the heart of our Down syndrome. By focusing on research. Our project synergizes hematopoietic stem cells (HSCs) the expertise of Dr. Chris Sturgeon, within the fetal liver — the primary known for his work on human Figure: Trisomy 21 fetal hematopoietic stem cells have deficiencies that are typically associated with site of blood cell production during primary natural killer cells, and Dr. hematopoietic stem cells in aged individuals. prenatal development — we aim to Elvin Wagenblast, an expert in Down discover how the additional genetic syndrome fetal hematopoiesis. This material in individuals with Down syndrome impacts cell develcollaboration facilitates a comprehensive approach to tackle opment and function. the complex challenges associated with Down syndrome and enhances the potential for significant health outcomes improveUtilizing advanced technologies such as single-cell RNA sequencing, our team is profiling the gene expression and muta- ments through the identification of novel therapeutic interventions. tional landscape of these cells — one cell at a time. This highresolution analysis allows us to explore cellular heterogeneity in a way that was previously not possible. Moreover, our studies extend to examine the fetal liver microenvironment, assessing how it may foster preleukemic conditions. We are particularly interested in how natural killer cells, known for their roles in immune regulation and cytotoxicity, interact with other cellular components in the liver, potentially leading to dysfunctions such as liver fibrosis — a severe complication associated with TAM that can result in organ failure and death.
Our project aims to identify therapeutic targets to prevent the development of TAM, resolve associated liver fibrosis, and halt the progression to leukemia. Our approach seeks to shift away from chemotherapy treatment, which, while managing symptoms, do not prevent the transformation of TAM into leukemia and carry the risk of long-term health complications. Elvin Wagenblast, PhD Assistant Professor, Pediatrics and Oncological Sciences