Investigating Clonal Evolution in Fanconi Anemia
Abstract
Bone marrow failure (BMF) disorders affect both adults and children. BMF results in inadequate production of mature blood cells rendering patients susceptible to infection and dependent on blood transfusions. Many BMF disorders are also predisposed to the development of leukemia, which is often resistant to treatment. Fanconi anemia (FA) is a specific BMF disorder that is associated with a very high risk of leukemia. Since bone marrow transplantation (BMT) can cure the BMF and leukemia of FA but is also a high-risk procedure, identification of the patients who are committed to the earliest stages of leukemia development is crucial so that these patients can receive timely BMT. Therefore, the critical overarching problem addressed in this proposal is how to recognize the earliest stages of leukemia development in BMF to identify patients who would benefit from pre-emptive BMT. The FY22 BMFRP Idea Development Award Focus Area addressed in this work is understanding the causes and progression of BMF diseases. We have developed a new model system of human FA that captures the key hallmarks of this disease, in particular the blood stem cell failure that underlies BMF. In the preliminary work forming the basis of this proposal, by performing targeted modification of specific genes, we can also model FA-associated leukemia. Here, we aim to apply this system to understand the process of development of leukemia in FA. Our hypothesis is that FA patients acquire gene mutations in their blood stem cells that trigger the process of leukemia development before they start to show signs of symptoms of leukemia, providing an opportunity for early intervention. We will therefore sequence all of the genes in a group of FA patients to identify potential gene mutations that trigger the process of leukemia development. Once we identify candidate gene changes, we will test the effect of these mutations in causing leukemia-like outcomes in our human model system. When we have validated the effects of these gene changes, in the future, we could then screen for them in FA patients to pre-emptively find those at highest risk of leukemia. We believe that successful completion of these studies will form a new paradigm of research that can be broadly applied to many other BMF diseases. We believe that this project is innovative in that we combine information gained from gene sequencing in FA patients with our new cell model of human FA to identify and validate gene changes that initiate the cascade toward development of leukemia. Successful completion of this project will have a direct positive impact on FA patients by providing new approaches monitoring and screening for leukemia. We expect that these studies will be broadly impactful on the field of BMF research, as this general approach can be applied to the study of other forms of BMF that are also associated with a risk of leukemia.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310433
Entities
People
- Robert Rowe
Organizations
- United States Army