Mechanisms of Bone Marrow Failure and Leukemia Progression in Primary Human Fanconi Anemia Stem Cells in a Novel FA PDX Model
Abstract
The goal of this research proposal is to provide better treatments for Fanconi anemia (FA), an inherited bone marrow failure disorder that affects approximately 1 in 100,000 children. Children inherit this disorder from their parents. At a young age, their bone marrow fails to produce normal numbers of functioning blood cells, putting these children at risk for severe infections and making them dependent on blood transfusions. A a large number of blood transfusions has considerable side effects. In addition to suffering from failure of blood production, these children are also at a very high risk for developing leukemia as adolescents and young adults, as well as many other cancers. The best available treatment option for bone marrow failure and to prevent the development of leukemia is blood stem cell transplantation from a healthy sibling or an unrelated stem cell donor. This treatment can be harmful, especially when performed at a young age, and does not remove the risk of cancer in other organs. It is quite well known which genes in cells are affected that cause FA and understanding how these abnormalities cause FA is advancing. Less is known about what results in progression to leukemia and cancer, and no therapies exist that can slow, let alone halt, this process. Understanding factors that promote progression to leukemia and cancer is particularly relevant for those who may get exposed to toxic substances and radiation, such as active duty Service members. Blood stem cells in general and specifically those from FA patients do not grow in the culture dish, and FA mouse models do not fully model the disease process. In recent years, transplantation of leukemia and cancer into mice whose immune system has been altered so that they accept human cells has greatly helped the study of these tumors. However, for FA, these studies have been elusive as the immunodeficient mice fail to support FA stem cells. The Flavell laboratory at Yale has developed “humanized” immunodeficient mice that express human proteins critical to human blood stem cells instead of their murine counterparts. We have tested whether these mice would allow blood stem cells from patients with bone marrow failure disorders to home into the bone marrow space, survive long term, and have the same problems in making blood cells as in patients. Indeed, this model is the first to efficiently allow these sick blood stem cells to live in mice so that they can be studied, manipulated, and treated. With the ideal model in hand to now study FA, we have gathered a team of experts in FA (Drs. Kupfer and Nalepa), humanized mouse modeling (Drs. Halene and Flavell), and genetic manipulation of cells (Dr. Chen) to study FA and understand how FA turns into leukemia and cancer. Drs. Kupfer and Nalepa specifically are hematologists who treat children with bone marrow failure and leukemia, while Dr. Halene is a hematologist who treats adult patients with bone marrow failure and leukemia. Our joint goal is to better understand FA and eventually develop treatments that will allow doctors to better treat children and young adults with FA. We also hope that the results of our studies will help treat cancers in non-FA patients in whom the cancer has acquired abnormalities that are similar to those that cause FA.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810138
Entities
People
- Stephanie Halene
Organizations
- United States Army
- Yale University