Abstract 5275: A dynamic equilibrium of innate immune deaminases and deregulation in hematopoietic malignancies

Inflammatory cytokine responsive apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC3) cytosine deaminases have been shown to be deregulated during cancer evolution, presenting as gene expression changes and inclusion of distinct C-to-T mutation patterns. However, the exact mechanisms by which APOBEC3 enzymes promote cancer initiation and progression remain to be investigated, especially in hematopoietic malignancies. Building on our advanced sequencing data of healthy, pre-leukemic, and myeloproliferative neoplasm patient samples, we seek to uncover normal and malignant patterns of APOBEC3C overexpression in hematopoietic cells. Overexpression of lentiviral APOBEC3C in normal cord blood, healthy bone marrow, and myeloproliferative neoplasm (MPN) patient hematopoietic stem/progenitor cells (HSPCs) allows us to study the effects of deaminase dysregulation in the hematopoietic niche. These overexpression studies show novel differential gene expression changes, repetitive element alterations, RNA hyper-editing sites, and DNA mutation signatures induced by APOBEC3 mutagenesis. In addition to APOBEC3, we are exploring the upregulation of adenosine deaminase acting on RNA1 (ADAR1), as we have previously shown that these two innate immune deaminases are synchronously upregulated in the high-risk myelofibrosis (MF) stem cell population compared to normal aged bone marrow. We have discovered a co-regulatory relationship dependent on a delicate equilibrium between APOBEC3C and ADAR1, indicating a correlative association between the dysregulation of these essential deaminases and the initiation and progression of hematopoietic malignancies as indicated by survival statistics and gene expression changes. We will use this comprehensive study of innate immune deaminase deregulation to uncover predictive biomarkers and hallmarks of malignant transformation. Citation Format: Jane Marie Isquith, Inge Van der Werf, Jessica Pham, Thomas Whisenant, Ludmil Alexandrov, Catriona Jamieson. A dynamic equilibrium of innate immune deaminases and deregulation in hematopoietic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5275.