Miettinen, Juho J. and Kumari, Romika and Traustadottir, Gunnhildur Asta and Huppunen, Maiju-Emilia and Sergeev, Philipp and Majumder, Muntasir M. and Schepsky, Alexander and Gudjonsson, Thorarinn and Lievonen, Juha and Bazou, Despina and Dowling, Paul and O`Gorman, Peter and Slipicevic, Ana and Anttila, Pekka and Silvennoinen, Raija and Nupponen, Nina N. and Lehmann, Fredrik and Heckman, Caroline A. (2021) Aminopeptidase Expression in Multiple Myeloma Associates with Disease Progression and Sensitivity to Melflufen. Cancers, 13 (7). p. 1527. ISSN 2072-6694

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Abstract

Abstract: 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 Cancers 2021, 13, 1527. Cancers 2021, 13, 1527 2 of 21 was reduced by aminopeptidase inhibitors. These results indicate critical roles of aminopeptidases in disease progression and the activity of melflufen in MM.

Item Type:	Article
Additional Information:	Cite as:Miettinen JJ, Kumari R, Traustadottir GA, Huppunen M-E, Sergeev P, Majumder MM, Schepsky A, Gudjonsson T, Lievonen J, Bazou D, Dowling P, O`Gorman P, Slipicevic A, Anttila P, Silvennoinen R, Nupponen NN, Lehmann F, Heckman CA. Aminopeptidase Expression in Multiple Myeloma Associates with Disease Progression and Sensitivity to Melflufen. Cancers. 2021; 13(7):1527. https://doi.org/10.3390/cancers13071527
Keywords:	multiple myeloma; aminopeptidase; gene expression; melflufen;
Academic Unit:	Faculty of Science and Engineering > Biology Faculty of Science and Engineering > Research Institutes > Human Health Institute
Item ID:	17267
Identification Number:	https://doi.org/10.3390/cancers13071527
Depositing User:	Paul Dowling
Date Deposited:	01 Jun 2023 11:16
Journal or Publication Title:	Cancers
Publisher:	MDPI
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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