Faculty, Staff and Student Publications
Publication Date
2-18-2025
Journal
Cell Reports Medicine
Abstract
Multiple myeloma is a clonal plasma cell (PC) dyscrasia that arises from precursors and has been studied utilizing approaches focused on CD138+ cells. By combining single-cell RNA sequencing (scRNA-seq) with scB-cell receptor sequencing (scBCR-seq), we differentiate monoclonal/neoplastic from polyclonal/normal PCs and find more dysregulated genes, especially in precursor patients, than we would have by analyzing bulk PCs. To determine whether this approach can identify oncogenes that contribute to disease pathobiology, mitotic arrest deficient-2 like-1 (MAD2L1) and S-adenosylmethionine synthase isoform type-2 (MAT2A) are validated as targets with drug-like molecules that suppress myeloma growth in preclinical models. Moreover, functional studies show a role of lysosomal-associated membrane protein family member-5 (LAMP5), which is uniquely expressed in neoplastic PCs, in tumor progression and aggressiveness via interactions with c-MYC. Finally, a monoclonal antibody recognizing cell-surface LAMP5 shows efficacy as an antibody-drug conjugate and in a chimeric antigen receptor-guided T-cell format. These studies provide additional insights into myeloma biology and identify potential targeted therapeutic approaches that can be applied to reverse myeloma progression.
Keywords
Multiple Myeloma, Humans, Single-Cell Analysis, Plasma Cells, Animals, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, Mice, myeloma precursors, disease progression, scRNA-seq, scBCR-seq, LAMP5, MAT2A
DOI
10.1016/j.xcrm.2024.101925
PMID
39855192
PMCID
PMC11866523
PubMedCentral® Posted Date
1-23-2025
PubMedCentral® Full Text Version
Post-print
Graphical Abstract
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons, Otolaryngology Commons