Elevated clonal hematopoiesis in 9/11 first responders has distinct age-related patterns and relies on IL1RAP for clonal expansion.

Divij Verma, Rachel Zeig-Owens, David G Goldfarb, Leah Kravets, Kith Pradhan, Bradley Rockwell, Srabani Sahu, Susheian Kelly, Orsi Giricz, Sakshi Jasra, Yiyu Zou, Colette Prophete, Lidiane S Torres, Srinivas Aluri, Samarpana Chakraborty, Rajni Kumari, Shanisha Gordon-Mitchell, Jingli Wang, Alexander J Silver, Taylor M South, Sarah D Olmstead, Charles B Hall, Simone Sidoli, Ryan Bender, Ola Landgren, Lee M Greenberger, Amittha Wickrema, Advaitha Madireddy, Aditi Shastri, Eric M Pietras, Lindsay M LaFave, Anna Nolan, Mitchell D Cohen, Michael R Savona, Ulrich Steidl, David J Prezant, Amit Verma

Albert Einstein College of Medicine, Bronx, New York, United States. · pubmed

Paper

Abstract

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 to 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 cell while expanding Tet2-mutant CH clones in mice. 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.

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Research summary

The study identifies a link between environmental exposure and clonal hematopoiesis mutations, suggesting IL1RAP as a potential therapeutic target. This research is relevant as it explores the mechanisms of aging-related mutations and their implications for leukemia, contributing to understanding the root causes of age-related diseases.

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