Bone marrow breakout lesions act as key sites for tumor-immune cell diversification in multiple myeloma
The bone marrow microenvironment plays a crucial role in the development of multiple myeloma. As the disease progresses, malignant myeloma cells can evolve to survive outside the bone marrow. However, the processes underlying bone marrow independence and their consequences for immune control remain poorly understood. Here, we conducted single-cell and spatial multiomics analyses of bone marrow-confined intramedullary disease and paired breakout lesions that disrupt the cortical bone. These analyses revealed a distinct cellular microenvironment and architectural features of breakout lesions, characterized by extensive areas of malignant plasma cells interspersed with lesion-specific solitary natural killer and macrophage populations, as well as focal accumulations of immune cell agglomerates. Within these agglomerates, spatially confined T cell clones expanded alongside various immune cells, coinciding with the local genomic evolution of tumor cells. These analyses identify breakout lesions as a hotspot for tumor-immune cell interactions and diversification, representing a key event in myeloma pathogenesis.
Authors
- Laleh Haghverdi (ORCID: https://orcid.org/0000-0001-9280-9170)
- Lukas John (ORCID: https://orcid.org/0000-0001-8178-6890)
- Daniel Hübschmann (ORCID: https://orcid.org/0000-0002-6041-7049)
- Sabrina Horn
- Stefan Fröhling (ORCID: https://orcid.org/0000-0001-7907-4595)
- Philipp Reichert
- Llorenç Solé‐Boldo (ORCID: https://orcid.org/0000-0002-6974-9066)
- Stefanie Huhn (ORCID: https://orcid.org/0000-0003-1700-2371)
- Carsten Müller‐Tidow (ORCID: https://orcid.org/0000-0002-7166-5232)
- Simon Haas (ORCID: https://orcid.org/0000-0001-9227-2051)
- Simon Steiger (ORCID: https://orcid.org/0000-0002-4845-5042)
- Gunhild Mechtersheimer (ORCID: https://orcid.org/0000-0002-9442-3930)
- Johanna Wagner (ORCID: https://orcid.org/0000-0002-5087-3657)
- Alexandra M. Poos
- Alexander Brobeil (ORCID: https://orcid.org/0000-0002-1003-8577)
- Marc‐Andrea Baertsch (ORCID: https://orcid.org/0000-0002-4000-6904)
- Niels Weinhold (ORCID: https://orcid.org/0000-0002-5464-3234)
- Hartmut Goldschmidt (ORCID: https://orcid.org/0000-0003-0961-0035)
- Subarna Palit
- Pooja Sant (ORCID: https://orcid.org/0000-0001-9301-3211)
- Gerald Willimsky (ORCID: https://orcid.org/0000-0002-9693-948X)
- Jan‐Philipp Mallm (ORCID: https://orcid.org/0000-0002-7059-4030)
- Karsten Rippe (ORCID: https://orcid.org/0000-0001-9951-9395)
- Marc S. Raab (ORCID: https://orcid.org/0000-0003-4181-6922)
- Nina Prokoph (ORCID: https://orcid.org/0000-0002-6429-9895)
- Dominik Vonficht (ORCID: https://orcid.org/0000-0002-5579-7083)
- Raphael Lutz
- Christoph Rehnitz (ORCID: https://orcid.org/0000-0003-1537-8711)
- Sandra Sauer (ORCID: https://orcid.org/0000-0001-5552-3149)
- Andreas Trumpp (ORCID: https://orcid.org/0000-0002-6212-3466)
- Mirco Friedrich (ORCID: https://orcid.org/0000-0002-6401-3623)
- Wojciech Pepke (ORCID: https://orcid.org/0000-0001-9690-4511)
- Nina Hildenbrand (ORCID: https://orcid.org/0000-0002-3988-2018)
- Stefan Hemmer
- David M. Spranz (ORCID: https://orcid.org/0000-0002-3072-5390)
Institutions
- Queen Mary University of London (GB)
- German Cancer Research Center (DE)
- Max Delbrück Center (DE)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- Humboldt-Universität zu Berlin (DE)
- German Cancer Society (DE)
- National Center for Tumor Diseases (DE)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Freie Universität Berlin (DE)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- Science Immunology
- Published
- 2025-02-07
- DOI
- https://doi.org/10.1126/sciimmunol.adp6667
- Citations
- 17
- Primary Topic
- Multiple Myeloma Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 30.09