Targeting Genetic Pathways of Transformation of Bone Marrow Failure-Associated MDS
EvansMDS Young Investigator Award
Germline genetic factors that predispose to myelodysplastic syndrome (MDS) development are increasingly identified in pediatric and young adult patients with MDS. In contrast to MDS arising in older adults, MDS in younger patients is typically hypocellular and often arises in the context of bone marrow failure (BMF). A recent study of over fifteen hundred patients with MDS found that 4% of young patients with MDS undergoing stem cell transplant had unrecognized Shwachman Diamond Syndrome (SDS). This study not only highlighted the prevalence of this disorder in MDS, but also demonstrated frequent TP53 mutations in the context of SDS-associated MDS. Although the hematopoietic stressors differ, the study of BMF-associated TP53-mutated MDS may inform the general biological understanding and treatment of TP53-mutated MDS, including treatment-related secondary MDS (tMDS).
Shwachman Diamond syndrome (SDS) is a BMF predisposition syndrome caused by biallelic mutations in the SBDS gene, leading to hypomorphic expression of the SDS transcript. SBDS encodes a protein that functions in ribosome maturation and mitotic spindle stabilization. The risk of SDS patients developing MDS or AML has been estimated at approximately 30% by the time of 30 years of age. This study utilizes serially collected samples (ranging from 2-8 samples per patient) from 111 SDS patients affording us the opportunity to study somatic clonal burden in MDS as it develops. We posit that the germline genetic context of the marrow exerts conditional selective pressures affecting clonal adaptation specific to that context. The goals of our study are to gain mechanistic insights into the molecular pathogenesis of MDS in patients with genetic MDS predisposition, to characterize genomic markers for risk stratification informing medical management, and to develop effective therapies.