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Publications

Journal Article Research Support, Non-U.S. Gov't Ppublish 3 citations

PubMed: 38942927 DOI: 10.1038/s43018-024-00784-3

The proteogenomic landscape of multiple myeloma reveals insights into disease biology and therapeutic opportunities.

Nat Cancer 5(8):1267-1284

Authors: Evelyn Ramberger, Valeriia Sapozhnikova, Yuen Lam Dora Ng, Anna Dolnik, Matthias Ziehm, Oliver Popp, Eric Sträng, Miriam Kull, Florian Grünschläger, Josefine Krüger, Manuela Benary, Sina Müller, Xiang Gao, Arunima Murgai, Mohamed Haji, Annika Schmidt, Raphael Lutz, Axel Nogai, Jan Braune, Dominik Laue, Christian Langer, Cyrus Khandanpour, Florian Bassermann, Hartmut Döhner, Monika Engelhardt, Christian Straka, Michael Hundemer, Dieter Beule, Simon Haas, Ulrich Keller, Hermann Einsele, Lars Bullinger, Stefan Knop, Philipp Mertins, Jan Krönke

Affiliations

  • Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • Max Delbrück Center for Molecular Medicine, Berlin, Germany.
  • German Cancer Consortium (DKTK), partner site Berlin, DKFZ and Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Berlin Institute of Health, Berlin, Germany.
  • Internal Medicine III, University Hospital Ulm, Ulm, Germany.
  • German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Heidelberg, Germany.
  • Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
  • Department of Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany.
  • Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany.
  • Department of Medicine III, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany.
  • Freiburg University Hospital, Freiburg, Germany.
  • Medizinische Klinik, München Klinik Schwabing, Munich, Germany.
  • Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.
  • Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.
  • Nuremberg General Hospital, Nuremberg, Germany.
  • Paracelsus Medical School, Nuremberg, Germany.
  • Max Delbrück Center for Molecular Medicine, Berlin, Germany.
  • Berlin Institute of Health, Berlin, Germany.
  • Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • German Cancer Consortium (DKTK), partner site Berlin, DKFZ and Charité - Universitätsmedizin Berlin, Berlin, Germany.

Abstract

Multiple myeloma (MM) is a plasma cell malignancy of the bone marrow. Despite therapeutic advances, MM remains incurable, and better risk stratification as well as new therapies are therefore highly needed. The proteome of MM has not been systematically assessed before and holds the potential to uncover insight into disease biology and improved prognostication in addition to genetic and transcriptomic studies. Here we provide a comprehensive multiomics analysis including deep tandem mass tag-based quantitative global (phospho)proteomics, RNA sequencing, and nanopore DNA sequencing of 138 primary patient-derived plasma cell malignancies encompassing treatment-naive MM, plasma cell leukemia and the premalignancy monoclonal gammopathy of undetermined significance, as well as healthy controls. We found that the (phospho)proteome of malignant plasma cells are highly deregulated as compared with healthy plasma cells and is both defined by chromosomal alterations as well as posttranscriptional regulation. A prognostic protein signature was identified that is associated with aggressive disease independent of established risk factors in MM. Integration with functional genetics and single-cell RNA sequencing revealed general and genetic subtype-specific deregulated proteins and pathways in plasma cell malignancies that include potential targets for (immuno)therapies. Our study demonstrates the potential of proteogenomics in cancer and provides an easily accessible resource for investigating protein regulation and new therapeutic approaches in MM.

MeSH

Cells, Plasma Cells, Neoplasms, Proteogenomics, Multiple Myeloma, Therapeutics, Proteome, Plasma

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