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

IF 33.3 1区医学 Q1 ONCOLOGY

Cancer discovery Pub Date : 2025-10-01 DOI:10.1158/2159-8290.CD-24-1590

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

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引用次数: 0

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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9/11第一响应者的克隆造血能力升高具有明显的年龄相关模式，并依赖于IL1RAP进行克隆扩增。

环境暴露与癌前血液病有关，但明确暴露的队列研究有限。我们对9/11世界贸易中心（WTC）灾难中暴露于雾化粉尘和致癌物的大量第一反应者的血液样本进行了测序，并在控制了年龄、种族和性别后，与两组对照队列相比，观察到克隆造血（CH）突变的发生率明显更高。年轻暴露的第一反应者表现出非常规的CH突变，具有缺陷的DNA修复特征。与不含CH的WTC暴露应答者相比，有CH的WTC暴露应答者白血病风险升高（3.7% vs. 0.6%， OR=5.73）。暴露于从WTC部位收集的颗粒物会损害健康干细胞，同时扩大小鼠的tet2突变CH克隆。炎症传感器IL1RAP在小鼠CH中过表达，基因敲低可抑制突变克隆的体内生长。这项研究将离散的环境暴露与造血突变和白血病联系起来，确定IL1RAP是CH的一个新的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer discovery ONCOLOGY-

CiteScore

22.90

自引率

1.40%

发文量

838

审稿时长

6-12 weeks

期刊介绍： Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.