Abstract B027: Transcriptional and chromatin accessibility landscapes of hematopoietic progenitors in a mouse model of breast cancer

Abstract Hematopoietic abnormalities, including myeloid-skewing, anemia, and extramedullary hematopoiesis, are often observed in cancer patients, with evidence suggesting that they promote the development of myeloid-derived suppressor cells. However, our understanding of the mechanisms underlying these hematopoietic phenotypes remains incomplete. Here, using the MMTV-PyMT mouse model of breast cancer, we characterize the transcriptional and chromatin accessibility landscapes of bone marrow and spleen hematopoietic progenitors using single-cell ATAC+RNA sequencing. We show that for the uncommitted hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM), tumor growth induces a moderate upregulation of the myeloid-bias transcriptional signature and no significant chromatin accessibility changes. Compared to BM HSPCs, spleen HSPCs do not show a further upregulation of the myeloid-bias signature, and instead show the signature of Notch signaling, which has been associated with erythroid commitment. In addition, we also identify a cluster of spleen HSPCs in tumor-bearing animals with a transcriptional signature of mobilization, while our paired chromatin data suggest that AP-1 factors play a key role in HSPC mobilization. Furthermore, in contrast to the subtle tumor-induced changes in BM HSPCs, prominent transcriptional and chromatin changes are observed in dendritic cell (DC) progenitors, consistent with known cancer-associated DC defects. Our chromatin data also confirms, in an unbiased manner, that Stat3 and CEBP are both key contributors to DC defects. Overall, we provide a comprehensive dataset for understanding the hematopoietic consequences of cancer. Citation Format: Changxu Fan, Jun Wu, Xiaoyun Xing, Derek A. G. Barisas, Kyunghee Choi, Ting Wang. Transcriptional and chromatin accessibility landscapes of hematopoietic progenitors in a mouse model of breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B027.