Metabolic, Anti-apoptotic and Immune Evasion Strategies of Primary Human Myeloma Cells Indicate Adaptations to Hypoxia

• Published in: Molecular & cellular proteomics 2019-05, Vol.18 (5), p.936-953
• Main Authors: Janker, Lukas, Mayer, Rupert L., Bileck, Andrea, Kreutz, Dominique, Mader, Johanna C., Utpatel, Kirsten, Heudobler, Daniel, Agis, Hermine, Gerner, Christopher, Slany, Astrid
• Format: Article
• Language: English
• Subjects: Adaptation, Physiological; Apoptosis; Cancer Biology; Down-Regulation; Endoplasmic Reticulum - metabolism; Humans; Hypoxia; Immune Evasion; Immunohistochemistry; Mass Spectrometry; Metabolic adaptations; Metabolomics; Multiple Myeloma; Multiple Myeloma - immunology; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Neoplasm Proteins - metabolism; Primary human myeloma cells; Proteome - metabolism; Proteomics; Tandem Mass Spectrometry; Transcription Factors - metabolism; Tumor Cells, Cultured; Tumor Hypoxia; Up-Regulation
• ISSN: 1535-9476; 1535-9484
• DOI: 10.1074/mcp.RA119.001390

In-depth proteome profiling of primary human CD138-positive plasma cells, derived from bone marrow biopsies from patients with different stages of multiple myeloma, have been performed on a Q Exactive orbitrap. Analysis of the 6218 identified proteins using label-free quantification with the MaxQuant software revealed strategies adopted by myeloma cells to overcome limitations imposed by hypoxic conditions in the bone marrow microenvironment, including specific immune evasion mechanisms and metabolic adaptations. [Display omitted] Highlights •In-depth proteome profiling of primary human myeloma cells•Characteristics of myeloma cells are related to hypoxic bone marrow conditions•Myeloma cells show specific immune evasion strategies•Metabolic adaptations involve tumor and stroma cells Multiple Myeloma (MM) is an incurable plasma cell malignancy primarily localized within the bone marrow (BM). It develops from a premalignant stage, monoclonal gammopathy of undetermined significance (MGUS), often via an intermediate stage, smoldering MM (SMM). The mechanisms of MM progression have not yet been fully understood, all the more because patients with MGUS and SMM already carry similar initial mutations as found in MM cells. Over the last years, increased importance has been attributed to the tumor microenvironment and its role in the pathophysiology of the disease. Adaptations of MM cells to hypoxic conditions in the BM have been shown to contribute significantly to MM progression, independently from the genetic predispositions of the tumor cells. Searching for consequences of hypoxia-induced adaptations in primary human MM cells, CD138-positive plasma cells freshly isolated from BM of patients with different disease stages, comprising MGUS, SMM, and MM, were analyzed by proteome profiling, which resulted in the identification of 6218 proteins. Results have been made fully accessible via ProteomeXchange with identifier PXD010600. Data previously obtained from normal primary B cells were included for comparative purposes. A principle component analysis revealed three clusters, differentiating B cells as well as MM cells corresponding to less and more advanced disease stages. Comparing these three clusters pointed to the alteration of pathways indicating adaptations to hypoxic stress in MM cells on disease progression. Protein regulations indicating immune evasion strategies of MM cells were determined, supported by immunohistochemical staining, as well as transcript