Project Term
–
Washington University School of Medicine in St. Louis
St. Louis, MO
United States
Project Summary
Children get different types of leukemias than adults. Even if the leukemias look the same under the microscope, the mutations are different. We are trying to understand why the mutations are different and what the implications are for treatment.
We have found that changes in normal developing blood cells can determine whether a mutation will cause leukemia. For example, a mutation might only activate pathways that drive leukemias at one specific age. It may therefore only cause leukemia at that specific age. We have indeed identified several genes that are activated by infant leukemia mutations, but only shortly after birth. More recently, we have identified genes that actually protect fetal cells from leukemia formation, potentially accounting for the extreme rarity of leukemia prior to birth.
Differences between childhood and adult leukemias might have other implications. A mutation found only in children might require treatments that are unique to children. Work in our lab has identified mechanisms that help drive childhood-specific leukemias, which we are currently working to target.
Finally, we need better tools to model childhood leukemias so that drug screens use specimens that faithfully reflect the effects of childhood-specific mutations. We developed a new technology to efficiently model childhood leukemias using mouse cells. We are using this new technology to look for new drug targets that account for the unique properties of childhood leukemia.
By studying unique features of childhood leukemia - where and when they arise - we can develop treatments that account for unique properties of the childhood malignancies.
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.
Program
Grant Subprogram