Abstract PIK3CA mutation is one of the most common, recurrent genetic abbrations identified across multiple types of cancers. Such mutations sustain activation of PI3K/AKT/mTOR pathway, being considered reliable therapeutic targets; yet, the functional consequences still remain unclear. Angiosarcomas are a heterogenous group of soft-tissue sarcomas that form malignant endothelium with disorganized, irregular blood-filled vascular spaces, and a subset of the vascular tumors harbor PIK3CA mutations. In this study, we found that one of 11 canine angiosarcoma cells gave rise to vascular tumors in 3 of 3 mice in a series of xenograft experiments using a total of 86 immunodeficient BNX mice. Intriguingly, we also observed that xenografts developed lymphoproliferative tumors indicating a mouse B-cell origin in 3 of 4 mice from one case of canine patient-derived tumor xenografts: four tumor cases surgically implanted in a total of 16 BNX mice. Additionally, canine angiosarcoma cells induced splenomegaly with expansion of Ter-119+ erythroid progenitors in NSG mice. Canine angiosarcoma cells (two cell lines; DHSA-1426 and EFB) were capable of hematopoietic expansion and cell lineage differentiaton in vitro. Since PIK3CA mutations appear to promote cellular stemness and impairment of cell lineage differentiation, we determined if the mutations play a role in hematopoietic regulations of angiosarcoma cells. DHSA-1426 angiosarcoma cells were used to induce PIK3CA H1047R mutations using CRISPR/Cas9. We found that PIK3CA mutant angiosarcoma cells dysregulated AKT, ERK, and mTOR pathway with enrichement of inflammatory cytokines such as IL-6, IL-8, and MCP-1. Single cell RNA-seq data showed that PIK3CA mutant angiosarcoma cells established distinct single cell clusters representing immune reactions, cellular stemness, and lineage differentiation. Furthermore, PIK3CA mutant angiosarcoma cells developed malignant hematopoietic tumor in one of five BNX mice, while no evidence of hematopoietic tumor formation was found in mice transplanted with non-mutant cells. Altogether, our data suggest that angiosarcoma cells have the capacity to promote hematopoietic imbalance impacting on cellular ontogeny and lineage differentiation, potentially mediated by oncogenic PIK3CA. Our ongoing work is determining the mechanism of the cell fate decisions using bi-potential hematoendothelial progenitors derived from induced pluripotent stem cells harboring oncogenic PIK3CA. Citation Format: Emma Kozurek, Erin B. Dickerson, Jong Hyuk Kim. OncogenicPIK3CA promotes hematopoietic reprogramming and cell transdifferentiation developing hematopoietic malignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2586.