Abstract 763: Linking Down syndrome, clonal hematopoiesis, and autophagy

Abstract Down syndrome (DS) is the result of trisomy in chromosome 21 (T21) and is associated with an increased risk of diseases, particularly acute myeloid leukemia (AML). However, people with DS have variable disease risks and severities that have yet to be explained. We hypothesize that differing characteristics of clonal hematopoiesis (CH) may coincide with and/or contribute to poor health outcomes seen in people with DS and can help explain differences in disease outcome. To characterize CH, we use a rare-mutation detection technique called Duplex Seq, only requiring a blood draw to obtain the DNA from leukocytes. This targeted-sequencing tool uses a double-stranded tag to incorporate mutational data from both strands of DNA, enabling high sensitivity through the elimination of DNA processing errors. Using bioinformatics and COSMIC’s Cancer Gene Census, we have established differences in mutational patterns that enable us to distinguish people with DS from people without DS and characterize the variability among people with DS. Notably, protein-altering mutations in genes responsible for the differentiation of hematopoietic stem and progenitor cells are more prevalent among people with T21 than their counterparts who are disomic in chromosome 21 (D21). Coupling our genomic findings with other -omics approaches, we have drawn associations between the observed mutations and phenotypes of these individuals. Using mouse models of DS (Dp16, Dp17, and Dp10), we plan to investigate the susceptibility of CH and leukemogenesis with the use of a Moloney Murine Leukemia virus, expecting the mice modeling DS to have more prevalent CH and more leukemias. Furthermore, based on our analyses of leukocytic gene expression differences between people with DS with or without CH, we believe that people with DS have a varying reduction in autophagy that enables the presence of harmful CH and increased disease risk in some individuals. Using a GFP-LC3-RFP construct, we plan to quantify and compare basal autophagic flux between the mouse models of DS and their control littermates. This will enable us to draw the links between DS, CH, and autophagy. Future work will be centered around manipulating autophagy using transgenic mice and non-invasive interventions to see if deleterious phenotypes and risks to AML can be reversed. Overall, these studies offer a means by which disease risk in people with DS can be monitored through CH and a potential mechanism that can be altered by non-intrusive means to improve longevity and quality of life. Citation Format: Edward James Evans, Ross Granrath, Keith Smith, Joaquin Espinosa, Andrew Thorburn, James DeGregori. Linking Down syndrome, clonal hematopoiesis, and autophagy [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 763.