Aminopeptidase Expression in Multiple Myeloma Associates with Disease Progression and Sensitivity to Melflufen

Juho Miettinen, Romika Kumari, Gunnhildur Asta Traustadottir, Maiju-Emilia Anniina Huppunen, Philipp Sergeev, Muntasir M. Majumder, Alexander Schepsky, Thorarinn Gudjonsson, Juha Lievonen, Despina Bazou, Paul Dowling, Peter O'Gorman, Ana Slipicevic, Pekka Anttila, Raija Silvennoinen, Nina N. Nupponen, Fredrik Lehmann, Caroline Heckman

Research output: Contribution to journalArticleScientificpeer-review

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 was reduced by aminopeptidase inhibitors. These results indicate critical roles of aminopeptidases in disease progression and the activity of melflufen in MM.
Original languageEnglish
Article number1527
JournalCancers
Volume13
Issue number7
Number of pages21
ISSN2072-6694
DOIs
Publication statusPublished - Apr 2021
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 3122 Cancers
  • Multiple Myeloma
  • Translational Medical Research
  • 1184 Genetics, developmental biology, physiology
  • Gene expression
  • 1182 Biochemistry, cell and molecular biology
  • Aminopeptidases
  • Proteomics
  • Flow cytometry
  • 318 Medical biotechnology
  • Drug sensitivity and resistance testing
  • multiple myeloma
  • aminopeptidase
  • gene expression
  • melflufen

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