First responders who worked at Ground Zero in the aftermath of the 2001 attacks on the World Trade Center in New York City were three times more likely to have genetic changes associated with an increased risk of blood cancer compared with other first responders or members of the public who were not exposed to Ground Zero. Moreover, younger first responders (under age 60) who had worked at the site not only showed these genetic changes, which are rarely seen in people under 70, but the changes were unlike any previously seen in this condition, which commonly occur during normal ageing. Ground Zero first responders with these genetic changes have as much as a five-fold increased risk for leukaemia. Interestingly, when researchers exposed laboratory mice to dust from Ground Zero at a level equivalent to what first responders were exposed to in an eight-hour shift, the mice developed the same genetic changes seen in the responders. In particular, exposing the mice to the toxic dust led to overproduction of a protein called IL1RAP, which stimulates inflammation and increases the risk of cancer development. Deleting the gene for this protein halted the precancerous genetic changes and expansion of mutant blood cells. “Our study has shown not only an increased risk of developing leukaemia in Ground Zero-exposed first responders, but also a distinct spectrum of precancerous genetic changes in younger exposed responders,” said principal investigator Divij Verma, PhD, of Albert Einstein College of Medicine in the Bronx, New York. “We have also demonstrated that inflammation induced by exposure to toxic dust is the likely mechanism for these genetic changes, and that turning off the IL1RAP gene, in particular, may be a promising strategy to delay or inhibit the development of these genetic changes or prevent progression to leukaemia.” The genetic changes, known as clonal haematopoiesis (CH), have no signs or symptoms and are generally detected only when a person undergoes genetic testing for another condition such as a solid tumour or an unexplained low blood count. CH occurs in about 10% of people aged 70 and older, but is rare in people under 70. Studies have shown that people with CH have about a 1% per year chance of developing leukaemia or another blood cancer; they are also at elevated risk for heart and liver diseases. Dr. Verma and his colleagues collected blood samples from 988 firefighters and emergency medical personnel who were exposed to high levels of airborne dust, gases, and potential cancer-causing substances at Ground Zero and examined their genomes to determine how many had CH and how many of those with CH developed leukaemia. On average, the blood samples were collected 10 years after exposure; at the time of the blood draw, the responders’ median age was 56. The investigators then compared the Ground Zero-exposed responders with 255 firefighters who had not been at the site but had occupational exposures to pollutants and potentially toxic substances, and to 195 people from the general population who were not first responders and had not been at Ground Zero. They found that 14% of the exposed first responders had CH, compared with 7% of firefighters and other people who had not been at Ground Zero. Even though DNMT3A and TET2 were the two most common mutated genes in Ground Zero-exposed responders, the subsequent spectrum of mutations was distinct in younger Ground Zero-exposed responders (i.e., those now aged under 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%), which have not been reported in any previous CH studies. Notably, in the firefighters and other first responders who had no Ground Zero exposure, the risk of having CH was the same as for people who were not first responders and had not been to the site. Among Ground Zero-exposed first responders with CH, 3.7% developed leukaemia, compared with 0.6% of those in the non-exposed comparison groups. Compared with exposed first responders without CH, those with CH had more genetic changes indicating an elevated risk for leukaemia or another blood cancer, as well as increased levels of neutrophils and monocytes (types of white blood cells) and red cell width suggestive of greater inflammation. All Ground Zero-exposed first responders with CH are being contacted and invited to visit the hospital to identify any health problems as early as possible and initiate treatment, if necessary, Dr. Verma said. He and his team are conducting further research to identify any differences in exposures and their effects among first responders who worked at Ground Zero during the first three days of the disaster versus those who were there later. They are also working to identify the specific toxic components of the dust collected from Ground Zero, the mechanisms by which it causes genetic changes in exposed people, and whether these mechanisms and their effects are unique to Ground Zero exposure or have similarities with those seen in people exposed to wildfires, burn pits, and other environmental exposures.
A limitation of the study is that while deleting the gene for IL1RAP halted precancerous genetic changes in mice, no studies have yet been done to show whether this strategy will work in people. However, Dr. Verma said, IL1RAP is a potentially important target, as it inhibits signalling from several mediators of inflammation. Targeting IL1RAP holds significant potential for reducing inflammation and combating inflammation-driven malignancies, he said.
**Source:** [ASH](https://www.hematology.org/newsroom/press-releases/2024/studies-highlight-progress-in-preventing-and-treating-blood-cancers-and-pre-cancerous-conditions)