Bonnie K. Harrington

Introduction Targeted therapy against bcl-2 has proven efficacious in AML, notably with bcl-2 inhibitor venetoclax. Bcl-2 is one of several proteins in the bcl-

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is a clinical entity of aging humans that is characterized by cancer-associated mutations in white blood cells, without evidence of overt neoplasia. CHIP has been associated with an increased risk of hematologic cancers, cardiovascular disease, and all-cause mortality. We hypothesized that somatic mutations in specific genes associated with human CHIP would be detectable in the blood of aged dogs not known to have hematologic disorders. Methods: DNA from paired germline and whole blood samples from 93 geriatric canine patients affected by solid cancer were subjected to targeted next generation sequencing. Impact of the variants was predicted using Polymorphism Phenotyping version 2 software (PolyPhen-2, Harvard). Clinical and demographic data were extracted from medical records. Results: Somatic variants were detected in peripheral blood of four (4.3%) female dogs aged 12-15 years. Affected genes were ASXL1, KIT, SF3B1, TET2, RUNX1, and PPM1D. The variant in PPM1D was a nonsense mutation, while the other five variants were single nucleotide non-synonymous variants in protein coding regions of the genes. Following analysis by PolyPhen-2, the single nucleotide variants in KIT and SF3B1 were predicted to be benign, while the variants in ASXL1, TET2, and RUNX1 were predicted to be damaging. Conclusion: These results support the presence of variants in CHIP-associated genes in geriatric canids at a frequency similar to that observed in people, and the dog represents the first species in which the genetic lesion of CHIP has been documented. Further investigations are needed to confirm the association of this genetic lesion with clinical outcomes. Citation Format: Kimberley N. Sebastian, Hatice Gülçin Özer, Cory Howard, Laura Chadsey, Arletta Lozanski, Tzyy-Jye Doong, Gerard Lozanski, Wenjuan Ma, William C. Kisseberth, John C. Byrd, Bonnie K. Harrington. Clonal hematopoiesis of indeterminate potential in the companion dog [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1620.