A Cellular Proteome Map of Human Multiple Myeloma.

Background and Aims: Molecular profiling identifies proteins characteristically deregulated in malignant diseases. Characteristic biomarkers may be useful to support diagnosis and patient stratification, while the recognition of aberrant cell activities and cell survival strategies may lead to the development of specifically designed pharmacologic strategies. We therefore performed proteomic profiling of primary human multiple myeloma (MM) cells in order to define the impact of protein expression abnormalities in MM.

Methods: Plasma cells were isolated from bone marrow of patients with MM or MGUS and forwarded to proteome analysis based on 2D gel electrophoresis in addition to shotgun analysis by nano-LC-MS/MS. Erythrocytes, platelets and plasma as well as quiescent and activated lymphocytes, monocytes, endothelial and dendritic cells from healthy donors were processed in an identical manner for comparative analysis. The resulting data were interpreted with the aid of a homemade SQL database.

Results: Among about thousand proteins identified in MM cells, we found aberrant expression of proteins involved in fatty acid beta-oxidation (VLCAD), unfolded protein response/ER-stress (ARMET protein, cytosol aminopeptidase), oxidative stress (ste20/oxidant stress responsive kinase 1), interferon response (MX1), iron uptake (transferrin receptor/CD71), DNA modification (transforming protein ERG, methyltransferase-like protein 7A), apoptosis and survival (apoptosis-inducing factor 1, hsp75), protein synthesis (ribosome-binding protein, Unc-13 D), cell adhesion (CD9/tetraspanin-29, LYRIC/metastatic adhesion protein), signaling (sts-1) and cell-cell interaction (Cystatin F, basigin/collagenase stimulatory factor, stem cell growth factor, small inducible cytokine B7, PD-ECGF/Gliostatin).

Conclusion: The presently applied proteome analysis strategy, based on the systematic investigation of purified primary human cells, allowed us to find characteristic alterations in MM cells. Several proteins directly relate to known aberrant cell activities such as elevated protein synthesis and secretion resulting in ER-stress, which makes the cells sensitive to proteasome inhibitor treatment. Work is in progress to use quantitative assessment of such proteins for patient stratification, identification of response predictors, and biomarkers for the distinction of MM and MGUS.