Abstract 2555: Multimodal atlas of cellular senescence in human bone marrow reveals insights into aging and multiple myeloma

Abstract Hematologic malignancies, such as multiple myeloma, exhibit a markedly increased incidence with age and are profoundly influenced by the bone marrow microenvironment. The aged microenvironment can lead to the accumulation of senescent cells, characterized by permanent cell cycle arrest and a pro-inflammatory secretory phenotype. Despite its significance in age-related diseases, the role of senescent cells in the bone marrow microenvironment and their impact on aging and hematologic malignancies remain poorly understood.As part of the Cellular Senescence Network (SenNet), we created a multimodal atlas to characterize senescent cells in the human bone marrow using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics. Analysis of 55 scRNA-seq samples from healthy donors (aged 25-84) revealed that mesenchymal cells exhibited the strongest senescence signatures, which were elevated in aged individuals. While monocytes also displayed senescence signatures, they did not show an age-associated increase. Hematopoietic stem cell (HSC) subpopulations showed senescent profiles, suggesting that senescence spans multiple cell types in the bone marrow.Using the Xenium spatial transcriptomics platform, we profiled the bone marrow microenvironment in 17 samples from 15 healthy donors across a similar age range. We identified 32 distinct cell types and uncovered putative senescent subpopulations in plasma cells and vascular smooth muscle cells. Our analysis revealed 9 unique cellular neighborhoods, some anchored around established niches like the endosteum and arteriole, while others suggested novel niche candidates such as adipocytes, early myeloid progenitors, and megakaryocytes. Aging was associated with significant microenvironment remodeling, including increased mature myeloid cell types and lymphoid aggregates, along with a decline in lymphoid and progenitor populations.In 22 multiple myeloma samples from 15 untreated and 4 relapsed patients, we found significant microenvironment changes, such as the formation of plasma cell-rich pockets. These neighborhoods were enriched with monocytes and CD8 T cells, the latter showing elevated expression of exhaustion markers. In agreement with our neighborhood analysis, monocytes and CD8 T cells were found in closer proximity to plasma cells in samples with high tumor burden. Mesenchymal stem cells near plasma cells also showed increased senescence signatures compared to age-matched controls.Overall, our findings illuminate the senescent landscape of the bone marrow and provide a resource for understanding its role in aging and multiple myeloma. Citation Format: Wen-hung Chou, Julia T. Wang, Xiang Li, Kapur B. Dhami, Daniel Rapp, André Luiz N. Targino da Costa, Andrew Houston, Xiyi Wei, Yuting Zhao, Maede Shahin, Yizhe Song, Xiangwei Fang, Julie Fortier, Yuwei Zhang, Matthew Wyczalkowski, Reyka G. Jayasinghe, Kelsey Gallant, Michael Slade, Karolyn A. Oetjen, Kiran Vij, Daniel C. Link, Ryan Nunley, Ravi Vij, Feng Chen, Ryan C. Fields, Li Ding. Multimodal atlas of cellular senescence in human bone marrow reveals insights into aging and multiple myeloma [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 2555.