Elevated Clonal Hematopoiesis in Environmentally Exposed Responders Has Distinct Age-Related Patterns and Relies on IL1RAP for Clonal Expansion

• Published in: Blood 2024-11, Vol.144 (Supplement 1), p.943-943
• Main Authors: Verma, Divij, Owens, Rachel Zeig, Goldfarb, David G, Pradhan, Kith, Sahu, Srabani, Kelly, Susheian, Giricz, Orsi, Jasra, Sakshi, Zou, Yiyu, Prophete, Colette, Torres, Lidiane, Aluri, Srinivas, Chakraborty, Samarpana, Gordon Mitchell, Shanisha, Kumari, Rajni, Wang, Jingli, Silver, Alexander J, Hall, Charles, Bender, Ryan, Landgren, Ola, Greenberger, Lee, Madireddy, Advaitha, Shastri, Aditi, Lafave, Lindsay, Nolan, Anna, Savona, Michael R., Steidl, Ulrich, Prezant, David, Verma, Amit
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2024-194127

Environmental exposures have been postulated to affect the pathogenesis of many human diseases including blood cancers and predisposition conditions such as clonal hematopoiesis (CH). There are few systematic studies that have determined the magnitude of CH in well-defined cohorts of environmental exposures. We conducted deep sequencing analysis of 988 World Trade Center (WTC) responders (firefighters and emergency medical service) exposed to high levels of aerosolized dust, gases, and potential carcinogens associated with the World Trade Center (WTC) disaster to determine the prevalence of CH and the association between CH and leukemia. First, the CH prevalence among WTC-exposed responders was compared to that of two comparison cohorts: non-WTC-exposed firefighters (n=255) and non-WTC-exposed controls (n=195; individuals from the general population). We observed a significantly higher prevalence of CH among WTC-exposed responders (14%) versus non-WTC-exposed firefighters (7%, odds ratio (OR)=3.38; 95% CI 1.90-6.34) and non-WTC-exposed controls (general population; 7%, OR=3.57; 95% CI 1.94-7.01) after controlling for age, race, and sex. Interestingly, we did not observe an increased CH burden among non-WTC-exposed firefighters compared to controls from the general population, contrary to the anticipated increase due to occupational exposure to toxic smoke. Even though DNMT3A and TET2 were the two most common mutated genes, the subsequent spectrum of mutations was distinct in younger WTC-exposed responders (age < 60) and included APC (6.6%), KMT2D(4.8%), ATM (4.8%), PIK3CA (4.2%) CREBBP (3.0%), BRCA2 (2.4%), ERBB4 (2.4%), and ARID1A (2.4%). Additionally, the risk of developing leukemia was elevated (3.7% vs 0.6%; OR, 5.73; 95% CI, 1.24-26.21) in WTC-exposed responders with CH compared to those without CH. Moreover, CH in younger responders was characterized by a higher variant allele frequency (Median VAF of 28% vs 13%) with 70% of the mutations being missense mutations. Analysis of overall mutational signatures in WTC-exposed responders demonstrated an enrichment of aging-related (Signature 1A) and defective homologous-recombination-based repair or BRCA1/BRCA2 mutation-associated signatures in younger WTC-exposed responders. We also observed increased levels of neutrophils, monocytes, and red cell width (RDW) in WTC-exposed responders with CH compared to those without CH, suggestive of elevated inflammation. We created an in vivo model mimicking an 8-hour