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

Program: Oral and Poster Abstracts
Type: Oral
Session: 503. Clonal Hematopoiesis, Aging, and Inflammation: Causes and Consequences
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Adult, Translational Research, CHIP, Clinical Research, Hematopoiesis, Diseases, Myeloid Malignancies, Biological Processes, Technology and Procedures, Study Population, Human, Animal model
Monday, December 9, 2024: 4:30 PM

Divij Verma, PhD1, Rachel Zeig Owens2*, David G Goldfarb3*, Kith Pradhan, PhD4*, Srabani Sahu, MS1*, Susheian Kelly2*, Orsi Giricz, PhD, MSc5,6, Sakshi Jasra, MD7, Yiyu Zou2*, Colette Prophete8*, Lidiane Torres9*, Srinivas Aluri, PhD10, Samarpana Chakraborty11, Shanisha Gordon Mitchell1*, Rajni Kumari12*, Jingli Wang, PhD8*, Alexander J Silver, BA, PhD13,14, Charles Hall, PhD2*, Ryan Bender15*, Ola Landgren16, Lee Greenberger17*, Advaitha Madireddy, PhD18, Aditi Shastri, MD1,19, Lindsay Lafave, PhD8*, Anna Nolan20*, Michael R. Savona, MD21*, Ulrich Steidl8,22, David Prezant23* and Amit Verma, MD1,24

1Blood Cancer Institute, Department of Oncology, Albert Einstein College of Medicine, Bronx, NY
2Albert Einstein College of Medicine, Bronx, NY
3Montefiore Medical Center, Bronx, NY
4Department of Oncology, Blood Cancer Institute, Albert Einstein College of Medicine, Bronx, NY
5Albert Einstein College of Medicine, Bronx
6The Leukemia & Lymphoma Society, Rye Brook, NY
7Department of Hematology/Oncology, University of Vermont Larner College of Medicine, Burlington, VT
8Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY
9Department of Cell Biology, Albert Einstein College of Medicine, New York, NY
10Montefiore Einstein Cancer Center, Blood Cancer Institute, Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY
11Albert Einstein College of Medicine, New York, NY
12Albert einstein College of Medicine, Bronx
13Vanderbilt University Medical Center, Nashville, TN
14Vanderbilt University School of Medicine, Nashville, TN
15Genoptix, Carlsbad, CA
16Sylvester Comprehensive Cancer Center, Miami, FL
17Leukemia and Lymphoma Society, New York
18Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ
19Montefiore Einstein Comprehensive Cancer Center, Blood Cancer Institute, Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY
20NYU School of Medicine, New York, NY
21Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN
22Department of Oncology, Montefiore Medical Center, Bronx, NY
23FDNY World Trade Center Health Program, Fire Dept. of the City of New York (FDNY), New York, NY
24Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY

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 responder work-shift at the WTC site for responders by administering a single dose of WTC-particulate matter (WTC-PM; chemically characterized matter obtained from Ground Zero) to mice via oropharyngeal instillation. We found that administration of WTC-PM led to impaired hematopoietic stem cell (HSC) function in vivo. We utilized a non-conditioned Tet2+/- bone marrow transplantation-based model of CH and found that WTC-PM exposure accelerated the growth of the mutant clones and increased the expression of IL-1 receptor accessory protein (IL1RAP), a sensor and mediator of inflammatory signals, on Tet2+/- hematopoietic stem-progenitor cells (HSPCs). Heterozygous deletion of Il1rap significantly decreased the expansion of Tet2-mediated CH clones after WTC-PM exposure in vivo. Strikingly, the previously reported resistance to inflammation-mediated toxicity exhibited by Tet2-mutant cells was lost in Il1rap deficient Tet2-mutant cells.

Our study demonstrates a novel spectrum of CH mutations in younger, environmentally exposed responders. It shows an increased risk of developing leukemia, increased inflammation, and identifies IL1RAP as a mediator of CH progression and a potential therapeutic target in this context. Our study reveals associations between environmental exposures, hematopoietic stem cell clonal dynamics and somatic blood mutations using a unique cohort with well annotated exposure and clinical histories.

Disclosures: Bender: Neogenomics: Current Employment. Landgren: Adaptive: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees.; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees. Shastri: Ryvu therapeutics: Research Funding; Jassen: Consultancy; NACE & PeerView: Honoraria; Geron: Speakers Bureau; Gilead, Rigel, Kymera: Consultancy; Kymera: Research Funding. Savona: Incyte: Other: Grants or Contracts from entity; MDSF Foundation BOD: Membership on an entity's Board of Directors or advisory committees; Karyopharm, Ryvu, Empath Biosciences: Current equity holder in publicly-traded company; Boehringer, Empath Biosciences: Patents & Royalties; Astex: Other: Grants or Contracts from entity; Abbvie, BMS, CTI, Forma, Geron, GSK, Rigel, Taiho, and Treadwell: Consultancy. Steidl: Stelexis: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Pieris Pharmaceuticals: Consultancy; Vor Biopharma: Consultancy; Trillium Therapeutics: Consultancy; Novartis: Consultancy, Research Funding; Roche: Consultancy; Pfizer: Consultancy; Aileron Therapeutics: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Bayer Healthcare: Consultancy, Research Funding; Celgene: Consultancy. Verma: Calico: Membership on an entity's Board of Directors or advisory committees; Halia: Research Funding; Curis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioconvergent health: Current equity holder in private company; Bristol Myers Squib: Research Funding; Prelude: Research Funding; Clinstreet: Current equity holder in private company; Stelexis: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees.

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