Abstract
Multiple myeloma (MM) is a highly refractory hematologic malignancy for which targeted immunotherapy and stem cell transplant have shown great promise. Two key challenges in advancing treatment lie in identifying broadly representative tumor markers and understanding the how post-transplant bone marrow (BM) immune repopulation influences treatment outcomes. Recent technological developments in single-cell RNA-sequencing (RNA-seq) and probe-based spatial transcriptomic assays now allow us to perform deep molecular characterization, interrogating cellular heterogeneity and interaction at unprecedented granularity. My dissertation leverages these platforms to uncover therapeutic targets and enhance our understanding of transplant-induced bone marrow remodeling. First, I utilize scRNA-seq to analyze BM aspirates from MM patients, applying a high-throughput, unbiased pipeline to identify candidate MM marker genes, including novel markers not yet under clinical investigation and previously characterized as potential therapeutic targets. These findings were cross-validated using bulk RNA sequencing, flow cytometry, and proteomic mass spectrometry, confirming the ability of single-cell technologies to accurately capture marker expression despite sample size and sequencing depth limitations. Next, I focus on understanding how BM dysregulation impacts MM treatment outcomes, particularly after autologous stem cell transplantation (ASCT). We conducted scRNA-seq on post-transplant BM aspirates, alongside samples from newly diagnosed MM patients and healthy controls, revealing immune features linked to MM pathogenesis and transplant response. These included dysregulated NFκB signaling in MM plasma cells and naive B cells, increased T cell exhaustion, and altered myeloid signatures associated with tumor burden and survival outcomes. Using probe-based spatial transcriptomics, we further mapped the BM microenvironment, observing compartmentalization of lymphocyte- and progenitor-rich regions and disruption of early B cell developmental niches, which correlated with treatment outcomes. This study underscores the importance of the BM milieu in post-transplant responses and provides new insights into how spatial and immune dysregulation contribute to treatment resistance in MM. Together, these findings demonstrate the power of single-cell and spatial transcriptomics in uncovering new therapeutic targets and elucidating the complex BM microenvironment in MM, offering promising avenues for enhancing precision medicine in MM treatment.
Committee Chair
Li Ding
Committee Members
John DiPersio; Jennifer Foltz; Nathan Singh; Reyka Jayasinghe
Degree
Doctor of Philosophy (PhD)
Author's Department
Biology & Biomedical Sciences (Computational & Systems Biology)
Document Type
Dissertation
Date of Award
4-23-2025
Language
English (en)
DOI
https://doi.org/10.7936/v5md-gb97
Author's ORCID
https://orcid.org/0009-0007-0042-6457
Recommended Citation
Wang, Julia, "Advancing Precision Treatment of Multiple Myeloma with Single-Cell and Spatial Immune Profiling" (2025). Arts & Sciences Theses and Dissertations. 3468.
The definitive version is available at https://doi.org/10.7936/v5md-gb97