Childhood Cancer

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Describing the Biological Impacts of Gain-of-function SAMD9 Mutations

Institution: 
Vanderbilt University Medical Center
Researcher(s): 
Jason Schwartz, MD/PhD
Grant Type: 
Young Investigator Grants
Year Awarded: 
2018
Type of Childhood Cancer: 
General Pediatric Cancer
Project Description: 

Background: 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. 

Project Goal: 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 2022: We have created a novel pediatric MDS model system that contains mutated SAMD9 or SAMD9L from a special type of stem cell. It is important to have these new cell lines because cells that we can obtain from patients do not grow well or for a long time. We will perform several tests in our model system to determine why mutations in SAMD9 and SAMD9L cause blood stem cells to die. Together with our cell lines we have also developed a second set of tools through DNA cloning and CRISPR technology that will allow us to turn on or to turn off SAMD9 or SAMD9L without using interferon—an inflammatory substance in the cell that turns on many other cell processes including SAMD9 and SAMD9L. With these tools we have completed initial experiments that suggest that SAMD9 and SAMD9L are important in how cells communicate during inflammation and other immune responses. Our proposed experiments will further determine how disease-causing mutations in SAMD9 and SAMD9L disrupt communication in these important cellular pathways. Understanding how SAMD9/9L mutations effect the blood stem cells will help us determine the right treatment approach for patients with pediatric MDS, because some patients with SAMD9 or SAMD9L mutations may not need treatment at all.