Identifying Collaborating Factors Driving DDX41 Mutant Pathology in MDS - As we age, the efficiency of the hematopoietic system declines resulting in bone marrow failure symptoms in some individuals. Myelodysplastic syndromes (MDS) are disorders primarily affecting older adults and impact around 10,000 individuals annually in the United States. MDS arises due to dysfunction in hematopoietic stem and progenitor cells (HSPCs), leading to ineffective blood cell production and an elevated risk of progression to acute myeloid leukemia (AML). The mechanisms driving the onset and progression of MDS remain poorly understood. Studying the germline and somatic genetics of inherited bone marrow failure syndromes (iBMFS) offers valuable insights into the fundamental processes required to maintain healthy hematopoiesis. While the biology of iBMFS is shaped by specific genetic defects, many of the principles uncovered are broadly relevant to HSPC regulation. Individuals with germline heterozygous loss-of-function mutations in the ATPase DEAD-box Helicase 41 (DDX41) gene tend to develop MDS later in life, resembling the sporadic form of the disease. These patients often present with high-risk MDS characteristics, such as elevated blast counts and increased risk of transformation to AML. Paradoxically, they also tend to have a more favorable overall prognosis compared to others with transforming MDS. This suggests that DDX41-mutant MDS follows a uniquely aggressive yet somewhat protective disease trajectory. We propose that studying this atypical, late-onset iBMFS can reveal broader principles governing hematopoietic fitness and dysfunction during aging. Using a germline ddx41 HET mutant zebrafish that develops age-associated MDS-like symptoms, we uncovered elevated inflammation as well as stem cell stress and quiescence gene signatures enriched in HETs. We will test the hypothesis that DDX41 mutations synergize with age-associated inflammatory signaling and/or secondary somatic mutations to exacerbate hematopoietic dysfunction. In Aim 1, we will examine how DDX41 insufficiency cooperates with age- associated cGAS activity promotes HSPC malfunctioning. In Aim 2, we will explore how co-mutations of DDX41 with CUX1 contribute to aberrant differentiation. Gaining a better understanding of this pathway may lead to the discovery of biomarkers and therapeutic strategies applicable to both hereditary and sporadic forms of MDS.
