Alan B. Cantor, M.D., Ph.D.
2021 Funding recipient
Role of ANKRD26 Mutations in Familial MDS Predisposition
Discovery Research Grant 2021
Myelodysplastic syndrome (MDS) is a disease in which the body develops difficulty producing blood cells properly. This makes patients tired due to low red blood cells, bleed due to low platelets, and/or develop infections due to low white blood cells. Patients with MDS may need blood transfusions to maintain their health. MDS can also evolve into leukemia, a cancer of the blood. Despite the significant impact of MDS of patient’s lives, we still do not fully understand why and how MDS develops. This knowledge gap has impeded efforts to develop better tests and treatments.
MDS can sometimes run in families. In these cases, a mutation in a gene gets passed down through generations and predisposes affected members to getting MDS. Identifying the genes that are mutated can provide important clues as to how MDS develops. In addition, since individuals are born with the mutations but don’t typically develop MDS for many years, there is a window of opportunity to potentially intervene with medications or other treatments to prevent people who harbor these mutations from developing MDS.
This proposal studies a gene called ANKRD26. This gene was recently identified as a cause of familial MDS in which patients have low platelet counts since birth. The mutations cause too much of the ANKRD26 protein to be made by cells. However, very little is known about what ANKRD26 normally does. Moreover, it is not understood why too much ANKRD26 protein causes patients to have low platelet counts and develop MDS.
Our long-term goal is to further understand how MDS develops and to use this information to develop new treatments. The objective of this proposal is to further understand ANKRD26’s normal function in cells and how ANKRD26 over production leads to MDS. Moreover, it will begin developing a method to reduce the over-production of ANKRD26 in patient’s blood stem cells, which could someday be used to treat family members who inherit ANKRD26 mutations to prevent them from developing MDS.
One of the obstacles to further understanding ANKRD26’s role in MDS is the lack of an experimental animal system to study it. In preliminary studies, we generated a mouse model that produces too much ANKRD26. These mice have low platelet numbers and abnormal megakaryocytes, which are the bone marrow cells the produce platelets. The proposal will further characterize these mice to determine how well they mirror the human disease. It will also use various biochemical and cellular techniques to test our hypothesis that ANKRD26 normally helps cells respond to chromosome (DNA) damage and that too much ANKRD26 prevents the cells from properly correcting the damage. We hypothesize that this is why patients with ANKRD26 mutations are prone to developing MDS. Lastly, we will begin developing a gene therapy approach to reduce the overabundance of ANKRD26 in patient’s blood cells.
The successful completion of this study will lead to an improved understanding of how MDS develops in some patients, provide a new mouse model system to further study this process and test treatments, and begin development of novel gene therapy approach aimed at preventing patients from developing MDS who have inherited ANKRD26 mutations. As our collaborator has recently utilized a similar gene therapy approach in humans with sickle cell disease, positive results have the potential for rapid translation into early clinical trials.