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
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.
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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