Our lab is interested in understanding why children get cancer and how their cancers are different from adult cancers. Our primary focus is on leukemia, the most common cancer of childhood. Childhood and adult leukemias differ in some key ways:
- Adult leukemias often arise over the course of years or even decades. They usually have multiple mutations that are acquired through a process called clonal evolution. For example, suppose a blood forming stem or progenitor cell acquires a mutation that creates a selective advantage. This clone can then expand in size relative to normal stem cells. One of the mutant cells may acquire a second mutation that conveys further advantage. This process can occur iteratively until a fully transformed leukemia develops. Clonal evolution can be enhanced by the effects of age, inflammation and environmental exposures. Children, particularly young children, are not affected by these factors, yet they still get leukemia.
- Childhood leukemia, particularly infant leukemias, have fewer acquired mutations than adult leukemias. This is in line with the fact that childhood malignancies evolve over a shorter time period than many adult leukemias, and childhood leukemias are not driven by the deleterious effects of aging.
- The types of mutations that are found in childhood leukemias are generally different from the types found in adult leukemias.
- The cells that give rise to childhood and adult leukemias are often fundamentally different from one another. Fetal and adult stem cells express different genes, and they divide at different rates.
These differences all point to fundamentally distinct mechanisms of leukemia formation in young children and adults. By understanding why children get leukemia and how they differ from adult leukemias, we hope to improve treatment strategies.
Blood development and leukemogenesis
We are using mice to understand why mutations have different effects on blood forming hematopoietic stem cells (HSCs) and other progenitor cells at different stages of life. Mice allow us to model HSC development in a manner that is not possible in humans. Furthermore, we can modify the mouse genome to introduce leukemia-causing mutations. By studying mice, we have found that adult HSCs and progenitors are more susceptible than fetal HSCs/progenitors to mutations that are found in adult leukemia patients. Likewise, fetal blood progenitors are more sensitive than adult progenitors to mutations found in infant leukemia patients. These differences are largely related to age-related changes in gene regulation. In other words, a given mutation can turn on different genes in adult and fetal progenitors, and it therefore only leads to leukemia in one developmental context.
We are now using single cell RNA-sequencing and ATAC-seq to better understand the enhancers and transcription factors that control HSC development and leukemogenesis. This project will expose trainees to cutting edge genomic and stem cell biology techniques. It will provide deeper insights into the mechanisms that regulate hematopoietic development, and it will identify novel targets for therapy.
Inherited genetic variants as a cause of infant leukemia
Infant leukemias are difficult to treat malignancies. These leukemias often initiate prior to birth, and they have surprisingly few somatic mutations. In many cases, the leukemias have a somatic translocation involving the MLL gene, but they have no other somatic coding changes. It is not clear why such an aggressive malignancy can evolve so early in life with so few mutations. One possibility is that fetal/neonatal hematopoietic progenitors are exquisitely sensitive to MLL translocations (see above). Another possibility is that infant leukemia patients may have inherited genetic mutations that predispose their disease. Our collaborator in the Pediatrics Department, Dr. Todd Druley, has discovered that infant leukemia patients have abnormally high rates of potentially harmful single nucleotide variants (SNVs) in their germlines. These inherited variants may reduce the number of somatic mutations required to transform infant hematopoietic progenitors.
Our lab is using mouse models to determine which SNVs from infant leukemia patients are important for leukemogenesis and which are not. We have developed a novel gene editing system to functionally characterize combinations of predisposing SNVs in vivo. Trainees will gain exposure to cutting edge gene editing techniques, mouse genetics and stem/leukemia biology. These studies will improve our understanding of infant leukemia. They will lead to improved therapies and guide genetic counseling for infant leukemia patients.