Our goal is to develop new strategies to model and treat pediatric acute myeloid leukemia (AML). AML is a cancer of the blood that is often very difficult to treat. The therapies are toxic, and they have not evolved much in the past several decades. This lack of progress underscores why we need to study this disease – if we do not understand it better, we cannot treat it more effectively. The Magee lab has several ongoing projects related to AML biology. These are all basic research projects, but they have translational angles and opportunities.
Why are childhood and pediatric leukemias so different, and why does it matter?
Pediatric AMLs are caused by different mutations than many adult AML. This raises interesting questions, and it carries important implications. The questions center on how genes that regulate normal developmental changes in blood forming stem cells might also influence mechanisms of leukemia initiation. In other words, are there ages at which blood progenitors are easily transformed by a given mutation, and other ages at which they are not? How do these windows of heightened susceptibility open and close?
We have found that one mutation that causes pediatric AML, the MLL-ENL translocation, transforms neonatal blood progenitors more efficiently than both fetal and adult progenitors. In fact, the fetal programs are protective against AML, and when we re-activate fetal genes we can prevent AML from forming. We can even use this approach cure established AML. We are working to better understand the mechanisms. An implication of these differences is that pediatric leukemias might hijack different regulatory programs. For example, we have recently found that two mutations called FLT3-ITD and NUP98-HOXD13 can work together to hijack the interferon pathway (normally an inflammatory signal). These mutations cause very high-risk AML in children, but generally not adults. When we block interferon signaling, we can slow formation of AML caused by these two mutations. By studying how other pediatric mutation interactions, we can find additional targets for therapy.
In lay terminology
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. We think that changes that take place during normal blood development can help account for the differences. If we can give cells an “identity crisis” and make them “think” that they are a different age or identity than they really are, we might be able to negate the effects of certain mutations.
How can we better model unique properties of pediatric leukemia to arrive at more specific treatments?
Pediatric AML formation is difficult to study because the leukemias carry a variety of different mutations, in a variety of combinations, and they may arise from a variety of different cells at different stages of life. Right now, leukemias with mutations that make them hard to treat are all binned into the same high-risk category when we select therapies. We need new technologies that allow us to study each mutation, and combination of mutations, as a unique entity.
To address this problem, we have developed an innovative new strategy to model pediatric AML in mice. We can edit the genomes of mouse induced pluripotent stem cells (iPSCs) so that pediatric AML mutations can be activated at precise stages of development. We then generate chimeric mice, from the iPSCs, so that we can initiate AML at precise stages of development, with combinations of different mutations, without complex mouse breeding strategies. Furthermore, we can inactivate genes of interest to test whether they suppress or promote transformation. These approaches will allow study AML as a genetically complex disease, and they will provide tools for testing whether specific combinations of mutations sensitize leukemias to specific therapies.
We are pairing these models with human patient derived xenograft models. This allows us to confirm that mutations that we reverse into mouse cells accurately reflect human disease. We are collaborating with other labs on campus to use these models to understand unique metabolic and epigenetic properties of each pediatric AML.
In lay terminology
Childhood acute myeloid leukemias can have many different mutations in many different combinations. The combinations may determine whether a given therapy is effective or not. It is difficult to understand this level of complexity by simply studying patient samples, yet it is also difficult to model complexity in mice. We are developing new tools that will allow us to understand how combinations of mutations change biology and drug responses.
Why do some children get leukemia as a result of chemotherapy for a past cancer?
Secondary cancers are among the most feared consequences of chemotherapy treatment. Basically, the chemotherapy creates mutations and applies selective pressures that cause cancers – either myelodysplastic syndrome or AML – to form. We have been studying the role of a gene called KMT2C (also sometimes called MLL3) in these cancers. We have found that deletions in KMT2C can give blood forming hematopoietic stem cells an advantage over healthy stem cells. This can predispose to myelodysplastic syndrome or AML. Our ongoing work focuses on figuring out a mechanism for this advantage.
In lay terminology
In some cases, cancer treatments can lead to a second, unrelated leukemia. These therapy-related leukemias can be extremely difficult to treat. We have identified a gene, called KMT2C, that we believe is involved in this process. It changes how blood forming stem cells respond to chemotherapy. We are studying how it might contribute to therapy-related leukemias and how the leukemias might be prevented.