Teresa V. Bowman, Ph.D.
2021 Funding recipient
Delineating mechanisms of DDX41 insufficiency in MDS
Discovery Research Grant 2021
Myelodysplastic syndrome (MDS) is a disease caused by defects in blood-forming stem cells. Normally, these stem cells maintain the blood system by generating all mature blood cells. MDS stem cells are defective in this process, but paradoxically have an advantage over healthy stem cells. Mutations in the DEAD-box Helicase 41 (DDX41) gene are prevalent in familial adult-onset MDS. Despite carrying this mutation from birth, patients with DDX41 mutations typically do not develop disease symptoms until late in life. The late onset of MDS in these patients suggests that age-associated changes synergize with these mutations to promote blood stem cell dysfunction. Using a zebrafish ddx41 mutant, we unveiled a critical role for Ddx41 in regulating blood stem cell levels by suppressing an age-associated inflammatory signaling pathway. The defects in ddx41 zebrafish were only observed when levels of Ddx41 dropped below 50%. In the clinic, patients with germline DDX41 mutations often acquire a mutation in the second allele later in life. The zebrafish and human patient data imply that DDX41 dosage and age are important for blood stem cell dysfunction. In this proposal, we will use zebrafish and human cells to test if the aging environment cooperates with ddx41 mutations and assess how varying DDX41 levels negatively impacts blood stem cell function. We will also test if drugs that target the inflammatory pathway induced by DDX41 insufficiency can improve blood stem cell function. These studies will provide fundamental insights into cooperating events in DDX41 deficiency-driven pathology and identify potential novel MDS treatments.
Weinreb JT, Bowman TV, Clinical and Mechanistic Insights into the Roles of DDX41 in Haematological Malignancies, FEBS Letters, 2022, 1873-3468.14487 DOI: 10.1002/1873-3468.14487