A platform for deep topographic multiomic mapping of the bone marrow environment in multiple myeloma
- 1Botnar Research Centre, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, OX3 7LD, UK; Oxford Translational M
Abstract
Multiple myeloma is a genetically complex plasma cell malignancy in which profound intratumoral heterogeneity shapes disease progression and therapeutic resistance. Genomic subclones dynamically emerge and evolve under treatment pressure, yet their spatial organization within intact bone marrow remains poorly defined. We hypothesized that genetically distinct myeloma subclones occupy spatially discrete ecological niches associated with unique molecular and microenvironmental states. To test this, we here demonstrate a proof-of-concept spatial tri-omics workflow combining laser capture microdissection-based genomics and deep LC-MS/MS proteomics with single-cell spatial transcriptomics, integrated by digital co-registration of adjacent tissue sections. Applied to a myeloma bone marrow trephine, this approach enabled coordinated profiling of matched anatomical regions demonstrating that genomic, transcriptomic and proteomic profiles converged to define clone-specific microenvironmental programmes. We show that genetically distinct myeloma subclones occupy mutually exclusive regions of the same bone marrow biopsy. Remarkably, an aggressive del(17p) clone and a gain(12q) clone occupied defined anatomical territories within the same trephine-biopsied section, each clone exhibiting distinct genomic, transcriptomic, proteomic and cellular ecosystems. The del(17p) clone localized to a fibrotic, osteolytic and angiogenic niche enriched for activated stromal cells, osteoblasts, osteoclasts and immunoregulatory myeloid populations, whereas the gain(12q) clone occupied a comparatively quiescent marrow niche with limited stromal remodelling. Together, these findings demonstrate that genetically distinct myeloma subclones establish spatially and biologically discrete ecological niches through coordinated remodelling of stromal, immune and bone compartments, providing a framework for understanding clonal evolution within the bone marrow microenvironment.
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BibTeX
@misc{lu2026platform,
title = {{A platform for deep topographic multiomic mapping of the bone marrow environment in multiple myeloma}},
author = {J. Lu and C.-Y. Wang and S. Davis and E. Watson and C. Jiang and W. Baker and E. Calcutt and S. Gooding and J. Hester and F. Issa and P. Benevent Bellver and A. Lagana and C. Bjorklund and G. Napolitani and S. Griffin and A. Thakurta and K. Ramasamy and A. Sozanska and R. Cooper and D. Royston and N. Athanasou and A. P. Cribbs and R. Fischer and U. Oppermann and S. Rao},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.22.753531},
url = {https://www.biorxiv.org/content/10.64898/2026.09.22.753531v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - A platform for deep topographic multiomic mapping of the bone marrow environment in multiple myeloma
AU - J. Lu
AU - C.-Y. Wang
AU - S. Davis
AU - E. Watson
AU - C. Jiang
AU - W. Baker
AU - E. Calcutt
AU - S. Gooding
AU - J. Hester
AU - F. Issa
AU - P. Benevent Bellver
AU - A. Lagana
AU - C. Bjorklund
AU - G. Napolitani
AU - S. Griffin
AU - A. Thakurta
AU - K. Ramasamy
AU - A. Sozanska
AU - R. Cooper
AU - D. Royston
AU - N. Athanasou
AU - A. P. Cribbs
AU - R. Fischer
AU - U. Oppermann
AU - S. Rao
PY - 2026
DA - 2026/09/22
PB - bioRxiv
DO - 10.64898/2026.09.22.753531
UR - https://www.biorxiv.org/content/10.64898/2026.09.22.753531v1
AB - Multiple myeloma is a genetically complex plasma cell malignancy in which profound intratumoral heterogeneity shapes disease progression and therapeutic resistance. Genomic subclones dynamically emerge and evolve under treatment pressure, yet their spatial organization within intact bone marrow remains poorly defined. We hypothesized that genetically distinct myeloma subclones occupy spatially discrete ecological niches associated with unique molecular and microenvironmental states. To test this, we here demonstrate a proof-of-concept spatial tri-omics workflow combining laser capture microdissection-based genomics and deep LC-MS/MS proteomics with single-cell spatial transcriptomics, integrated by digital co-registration of adjacent tissue sections. Applied to a myeloma bone marrow trephine, this approach enabled coordinated profiling of matched anatomical regions demonstrating that genomic, transcriptomic and proteomic profiles converged to define clone-specific microenvironmental programmes. We show that genetically distinct myeloma subclones occupy mutually exclusive regions of the same bone marrow biopsy. Remarkably, an aggressive del(17p) clone and a gain(12q) clone occupied defined anatomical territories within the same trephine-biopsied section, each clone exhibiting distinct genomic, transcriptomic, proteomic and cellular ecosystems. The del(17p) clone localized to a fibrotic, osteolytic and angiogenic niche enriched for activated stromal cells, osteoblasts, osteoclasts and immunoregulatory myeloid populations, whereas the gain(12q) clone occupied a comparatively quiescent marrow niche with limited stromal remodelling. Together, these findings demonstrate that genetically distinct myeloma subclones establish spatially and biologically discrete ecological niches through coordinated remodelling of stromal, immune and bone compartments, providing a framework for understanding clonal evolution within the bone marrow microenvironment.
ER -