MDS-associated Splicing Factor Mutations sensitize to Necroptosis
EvansMDS Discovery Research Grant 2018
Myelodysplastic syndromes (MDS) are a group of blood diseases in which the blood-forming stem cells do not mature normally and many of the blood cells die for unclear reasons. MDS patients are at risk of developing bone marrow failure and anemia or myeloid leukemia. Treatments include chemotherapy to kill abnormal stem cells, treatment with stem cell growth factors and if necessary a bone marrow transplant with normal donor stem cells. Patients may also receive supportive care, which consists of blood transfusions to replenish red and white blood cells. MDS patients exhibit chronic inflammation in the bone marrow, which is thought to contribute to the abnormal blood cell maturation and increased cell death. This inflammatory microenvironment also leads to activation of the immune system and exacerbation of disease.
Recently researchers have discovered recurrent DNA mutations in genes known as splicing factors that are important in protein production. Our collaborators found TAK1 and caspase-8 are not expressed normally in blood cells of MDS patients and in MDS mouse models. We recognized that TAK1 and caspase-8 play important roles in the regulation of an inflammatory form of cell death called necroptosis. Our laboratory has shown that necroptosis results in inflammation, stem cell loss and bone marrow failure in the mouse. The goal of this proposal is to determine whether these MDS splicing factor mutations cause blood stem cells to undergo inflammatory cell death. We will determine whether mouse and human MDS cells that express mutant splicing factors are more sensitive to necroptosis in vitro. We will determine if we can rescue blood stem cell abnormalities in mutant mice by preventing necroptosis in vivo. Lastly, we will assess whether necroptosis inhibitors restore blood stem cell growth and maturation in MDS patient samples. If these studies implicate necroptosis in MDS pathogenesis, these findings could be rapidly translated to the clinic as necroptosis inhibitors are currently in clinical trial for other inflammatory diseases. Thus, the work proposed has the potential to provide immediate clinical benefit to MDS patients.