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Neonatal origins of pediatric AML

Jeffrey Magee

Jeffrey Magee


Washington University School of Medicine in St. Louis

Project Term: July 1, 2021 - June 30, 2026

Coming soon.

Lay Abstract

Our goal is to understand why children get a type of leukemia called AML. Childhood AML is different from adult AML. It is caused by different mutations, and it responds differently to treatment, but we do not know why. Our preliminary work suggests that as genes switch ‘on’ and ‘off’ during normal fetal and childhood blood development, the cells that give rise to AML will change accordingly. In other words, childhood and adult leukemias are different because normal blood cells change considerably between birth and adulthood. In the proposed experiments, we will test whether a series of normal, age-specific genetic switches can indeed underlie differences between childhood and adult AML. For example, we have shown that a gene that coordinates fetal blood development can actually protect the fetus from AML. After birth, this protection goes away and infants become susceptible to AML. We will test whether reactivating the fetal switch can cure infant AML using animal model systems. We have also found that inflammation can dramatically alter blood development just before birth, and it may make cells more susceptible to becoming AML. We will test whether perinatal inflammation can indeed promote some types of childhood AML. The overarching theme to these experiments is that developmental switches create vulnerabilities within the AML cells that are unique to childhood. If we can reprogram the switches, we can prevent or more effectively treat childhood AML. In addition to studying specific switches, we will develop a new system to recreate the earliest stages of AML formation in mice. Mice are a powerful tool for studying AML because one can observe each step of AML formation as it occurs in a living animal. Unfortunately, mice are laborious and expensive to use, and currently available models do not reflect all of the mutations that can potentially cause childhood AML. The system that we will develop will help circumvent these limitations. Upon completion of these aims, we expect to have a granular understanding of how blood cells develop shortly after birth and how developmental switches are hijacked to cause childhood AML. We expect to identify pathways that can be exploited therapeutically. Finally, we expect to generate a scalable system for studying childhood AML mutations – in combination with one another, in a living organism, at stages of life that reflect normal childhood development. This system will provide a powerful tool for drug development and screening, and it will facilitate efforts to develop therapies that target the unique properties of childhood leukemias.

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