A recent study has found that mutations in blood-forming cells may explain the increased risk for leukemia and other blood disorders among first responders exposed to the 9/11 World Trade Center (WTC) disaster site and its toxic dust. The study also points to a novel strategy for use against inflammation and blood disorders associated with environmental toxins. The research was published by Verma et al in Cancer Discovery.
“Our findings provide new insights into the long-term health impacts of environmental catastrophes, such as wildfires, and suggest targeted interventions for those affected by 9/11 or similar disasters,” said study leader Amit Verma, MD, Associate Director for Translational Science at Montefiore Einstein Comprehensive Cancer Center; Chair of Oncology at Albert Einstein College of Medicine and Montefiore Health System; and Professor of Oncology, Medicine, and Developmental & Molecular Biology at Einstein.
Toxic Dust and Unique Genetic Changes
The collapse of the WTC produced tremendous quantities of airborne particulate matter—a potent mixture of carcinogens and genetically toxic substances to which an estimated 400,000 responders, area workers, and residents were exposed. In previous studies, Montefiore Einstein researchers noted a higher incidence of cancers, cardiovascular disease, and other health problems among 9/11 first responders compared with the general population. However, few studies have examined how such environmental exposures may lead to blood cancers.
For this study, Einstein scientists sequenced blood samples from nearly 1,000 first responders who were exposed to the WTC site, along with blood from two control groups: 255 firefighters who were not at the WTC and 198 unexposed people in the general population. All samples were collected between December 2013 and October 2015.
The toxic 9/11 dust cloud was found to be associated with mutations in the blood cells of many responders. Compared with control-group individuals, WTC-exposed first responders had a significantly higher prevalence of clonal hematopoiesis (CH). Typically associated with aging, CH is a precancerous condition known to increase the risk of blood cancer and inflammation.
Overall, first responders with elevated CH mutations were nearly six times likelier to develop leukemia than those without the mutations. Exposure of mice to WTC dust led to high levels of inflammatory markers and an increase in mutant cells, suggesting that toxin-induced inflammation plays a key role in propagating the blood cells.
In addition, researchers found that younger first responders (< age 60) with elevated CH possessed a set of genetic mutations quite distinct from the classic mutations associated with age-related CH—indicating that the gene-altering toxins in WTC dust may contribute to cancer risk by accelerating the aging process.
Identifying a Protein Culprit: Preclinical Research
To learn how exposure to toxins is associated with CH mutations and increased leukemia risk, the researchers tested the dust collected from the WTC site in a mouse model. The dust caused an inflammatory response traced to the protein IL1RAP; the high levels of IL1RAP were associated with increased numbers of defective blood-forming stem cells—mimicking the high CH levels observed in the first responders. Of note, the researchers found they could prevent the rise in defective mutant cells by knocking out the gene that codes for IL1RAP.
“We now know that IL1RAP is a very attractive target for strategies aimed at suppressing the growth of these mutant clones,” said Dr. Verma, who is also the Susan Resnick Fisher Academic Chair in Brain Cancer Research at Einstein. He noted that IL1RAP has been implicated in many types of cancer as well in inflammatory and autoimmune diseases, and that several drugs aimed at inhibiting the protein are being evaluated in clinical trials.
“Our work has implications for people exposed to wildfires, air pollution, military burn pits, and many other exposures,” said Dr. Verma. “By screening toxin-exposed populations for CH, we could identify people at risk for blood cancers and then potentially treat or even prevent those cancers by targeting IL1RAP.”
Disclosure: For full disclosures of the study authors, visit aacrjournals.org.cancerdiscovery.
