Role of blood trait-associated genetic variants in early onset myelodysplastic syndromes
EvansMDS Young Investigator Award
As a future independent academic physician-scientist, I wish to identify the molecular underpinnings of disease heterogeneity in myelodysplastic syndromes (MDS) and use this information to develop novel therapies. I am seeking support through the EvansMDS Young Investigator Award (YIA) to augment my skillset in rigorous scientific approaches, facilitating my transition to a leading independent investigator in molecular hematology. Specifically, I propose to determine how non-coding genetic variants contribute to the development of early onset MDS and disease heterogeneity at the cellular and molecular levels.
Myelodysplastic syndrome (MDS) is largely a disease of aging, with a median age at diagnosis of 76 years.1 However, onset occurs before age 50 in approximately 1% of MDS cases. Early-onset MDS is often linked to known somatic mutations; yet, such mutations also commonly occur in older-age patients with MDS and few patients with early-onset MDS (12%) carry known germ-line variants associated with MDS-predisposing bone marrow failure syndromes (BMFS). In addition, less than 15% of patients diagnosed with BMFS based on clinical history and biochemical screening carry genetic mutations implicated in BMFS, and even those with identical variants exhibit heterogeneous MDS or BMFS phenotypes. First-degree relatives of MDS and AML patients <21 years old have 6.5-fold relative risk of AML/MDS compared to the general population, implicating hereditary factors in disease occurrence. Identifying other genetic contributors to the disease is critical to aiding early diagnosis and intervention to avert severe consequences of undiagnosed early-onset MDS.
The influence of genetic variability is typically assessed through genome-wide association studies (GWAS), but identification of causal variants by GWAS remains challenging because most variants associated with disease are in non-coding regions. Variants often concentrate in regulatory DNA within accessible chromatin where transcription factors (TF) can bind: indeed, 93% of variants within DNase hypersensitivity sites (DHSs) overlap a TF recognition sequence. DNA variation at a TF binding site can affect TF binding (occupancy), altering expression of the TF’s downstream targets. Because TFs exert critical regulation in hematopoiesis, aberrant TF occupancy could lead to development of MDS (pathologic variants) and/or heterogeneity of disease course and leukemia development (i.e., disease-modifying variants). We hypothesize that blood trait-associated non-coding variants, when located within active regulatory DNA elements, induce heterogeneity of bone marrow pathology by perturbing TF occupancy.