Describing the Biological Impacts of Gain-of-function SAMD9 Mutations
Pediatric myelodysplastic syndrome (MDS) is a disorder that causes low blood counts because specialized cells within the bone marrow, or the 'blood factory of the body', do not mature correctly. When this happens the cells cannot perform their intended job sufficiently. Currently, the only option for a cure for most children with pediatric MDS is a bone marrow transplant. Transplant is a difficult therapy with a less-than-ideal overall prognosis. Recently, our laboratory discovered that inherited mutations in two genes, SAMD9 and SAMD9L, play an important role in a child's risk of developing a specific type of MDS. These children have specifically lost DNA on chromosome 7 and this disease (also referred to as monosomy 7) is especially common in familial MDS. This association was not previously known. Furthermore, we have shown that the mutations in SAMD9 within a MDS patient typically result in a protein that performs its function at an increased level gain of function (GoF). This function decreases cell growth. The cells with a SAMD9 GoF mutation typically lose the copy of chromosome 7 containing the mutation. It is not well understood how, or by what trigger, this specific chromosome loss occurs.
We hypothesize that an inflammatory stimulus leads to increased SAMD9 production, which slows down cell growth at an increased rate if SAMD9 is mutated and thus pressures cells without the mutation (cells with monosomy 7) to out-compete the cells with the mutation. We plan to develop a pediatric MDS model system to test this hypothesis. Understanding this process would ultimately help determine which patients would benefit from a bone marrow transplant.
Project Update 2020
To better understand how mutations in SAMD9 and SAMD9L lead to chromosome 7 loss and myelodysplastic syndrome in children, we have developed important tools that we can use in the lab to ask specific questions about these mutations. These tools are special cell lines that grow for a long time so that we can complete many tests and repeat those tests to ensure we obtain accurate data. Having these renewable cell lines is important because cells that we can obtain from patients typically do not grow well or for a long time. With these cell lines, we will perform several tests to determine why mutations in SAMD9 and SAMD9L cause blood stem cells to die. Understanding how these mutations affect the blood stem cells will help us know how to predict if a particular mutation in these genes will cause a child many problems, or not, and help determine if that child needs difficult treatments like bone marrow transplantation, or not.