Aminopeptidase Expression in Multiple Myeloma Associates with Disease Progression and Sensitivity to Melflufen
| Autor: | Miettinen, Juho J., Kumari, Romika, Traustadottir, Gunnhildur Asta, Huppunen, Maiju-Emilia, Sergeev, Philipp, Majumder, Muntasir M., Schepsky, Alexander, Gudjonsson, Thorarinn, Lievonen, Juha, Bazou, Despina, Dowling, Paul, O`Gorman, Peter, Slipicevic, Ana, Anttila, Pekka, Silvennoinen, Raija, Nupponen, Nina N., Lehmann, Fredrik, Heckman, Caroline A. |
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| Přispěvatelé: | Institute for Molecular Medicine Finland, Helsinki Institute of Life Science HiLIFE, Digital Precision Cancer Medicine (iCAN), Hematologian yksikkö, Department of Oncology, HUS Comprehensive Cancer Center |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Proteomics
318 Medical biotechnology aminopeptidase 3122 Cancers 1184 Genetics developmental biology physiology Drug sensitivity and resistance testing lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens lcsh:RC254-282 Aminopeptidases Article melflufen multiple myeloma gene expression 1182 Biochemistry cell and molecular biology Flow cytometry Translational Medical Research |
| Zdroj: | Cancers, Vol 13, Iss 1527, p 1527 (2021) Cancers Volume 13 Issue 7 |
| Popis: | Multiple myeloma (MM) is characterized by extensive immunoglobulin production leading to an excessive load on protein homeostasis in tumor cells. Aminopeptidases contribute to proteolysis by catalyzing the hydrolysis of amino acids from proteins or peptides and function downstream of the ubiquitin–proteasome pathway. Notably, aminopeptidases can be utilized in the delivery of antibody and peptide-conjugated drugs, such as melflufen, currently in clinical trials. We analyzed the expression of 39 aminopeptidase genes in MM samples from 122 patients treated at Finnish cancer centers and 892 patients from the CoMMpass database. Based on ranked abundance, LAP3, ERAP2, METAP2, TTP2, and DPP7 were highly expressed in MM. ERAP2, XPNPEP1, DPP3, RNPEP, and CTSV were differentially expressed between relapsed/refractory and newly diagnosed MM samples (p < 0.05). Sensitivity to melflufen was detected ex vivo in 11/15 MM patient samples, and high sensitivity was observed, especially in relapsed/refractory samples. Survival analysis revealed that high expression of XPNPEP1, RNPEP, DPP3, and BLMH (p < 0.05) was associated with shorter overall survival. Hydrolysis analysis demonstrated that melflufen is a substrate for aminopeptidases LAP3, LTA4H, RNPEP, and ANPEP. The sensitivity of MM cell lines to melflufen was reduced by aminopeptidase inhibitors. These results indicate critical roles of aminopeptidases in disease progression and the activity of melflufen in MM. |
| Databáze: | OpenAIRE |
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