Elevated Clonal Hematopoiesis in 9/11 First Responders Has Distinct Age-related Patterns and Relies on IL1RAP for Clonal Expansion

Environmental exposures are linked to precancerous hematologic conditions, but studies in cohorts with well-defined exposures are limited. We sequenced blood samples from a large cohort of first responders exposed to the aerosolized dust and carcinogens from the 9/11 World Trade Center (WTC) disaster and observed a significantly higher prevalence of clonal hematopoiesis (CH) mutations when compared with two sets of control cohorts after controlling for age, race, and sex. Younger exposed first responders exhibited unconventional CH mutations, with defective DNA repair signatures. Leukemia risk was elevated (3.7% vs. 0.6%; OR = 5.73) in WTC-exposed responders with CH versus without CH. Exposure to particulate matter collected from WTC site impaired healthy stem cells while expanding Tet2-mutant CH clones in mice. The inflammation sensor IL1RAP was overexpressed in murine CH, and genetic knockdown inhibited mutant clone growth in vivo. This study links discrete environmental exposure to hematopoietic mutations and leukemia, identifying IL1RAP as a novel therapeutic target in CH.