Sickle cell disease (SCD) is marked by chronic hemolysis, systemic endothelial dysfunction, inflammation, and vascular occlusion, leading to severe pain, multi-organ damage, and a median lifespan of 48 years in high-income countries. Young adults with progressive heart, lung, or kidney damage are at heightened risk for premature death.
While many individuals with SCD are eligible for high-risk treatments like allogeneic hematopoietic stem cell (HSC) transplantation and autologous HSC gene therapy, some develop acute myeloid leukemia or other myeloid neoplasms afterward. These cancers often arise from premalignant autologous HSCs with somatic “clonal hematopoiesis” (CH) mutations present prior to treatment.
Research indicates that CH mutations give aging HSCs a growth advantage, increasing risks for myeloid leukemia and endovascular diseases. Preliminary data suggest that individuals with SCD develop CH at younger ages than the general population. We hypothesize that the higher prevalence of CH in SCD accelerates heart, lung, and kidney diseases.
To test this, we will assess CH prevalence in three multicenter cohorts of older children and adults with SCD (n = 2,645) and matched controls (n = 7,935). Using a novel sequencing assay, we will identify low-level CH mutations and investigate their association with organ diseases. Our completed whole-genome sequencing through the NIH NHLBI Trans-Omics for Precision Medicine (TOPMed) program will aid in examining genetic interactions between CH mutations and SCD outcome-related variants.
This project aims to clarify CH as a risk factor for organ disease in SCD, identify patients who could benefit from personalized organ protection strategies, and explore CH's role in myeloid leukemia development after SCD treatments.