Proteome alterations associated with transformation of multiple myeloma to secondary plasma cell leukemia

// Alexey Zatula 1, * , Aida Dikic 1, * , Celine Mulder 1, 2, * , Animesh Sharma 1, 3 , Cathrine B. Vagbo 1, 3 , Mirta M. L. Sousa 1 , Anders Waage 1, 4 , Geir Slupphaug 1, 3 1 Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Trondheim, Norway 2 Present address: University of Utrecht, Utrecht, Holland 3 PROMEC Core Facility for Proteomics and Metabolomics, Norwegian University of Science and Technology, NTNU, Trondheim, and the Central Norway Regional Health Authority, Stjordal, Norway 4 Department of Hematology, St. Olav’s Hospital, Trondheim, Norway * These authors have contributed equally to this work Correspondence to: Geir Slupphaug, email: geir.slupphaug@ntnu.no Keywords: multiple myeloma, secondary plasma cell leukemia, super-SILAC, quantitative proteomics Received: September 18, 2016     Accepted: November 30, 2016     Published: December 27, 2016 ABSTRACT Plasma cell leukemia is a rare and aggressive plasma cell neoplasm that may either originate de novo (primary PCL) or by leukemic transformation of multiple myeloma (MM) to secondary PCL (sPCL). The prognosis of sPCL is very poor, and currently no standard treatment is available due to lack of prospective clinical studies. In an attempt to elucidate factors contributing to transformation, we have performed super-SILAC quantitative proteome profiling of malignant plasma cells collected from the same patient at both the MM and sPCL stages of the disease. 795 proteins were found to be differentially expressed in the MM and sPCL samples. Gene ontology analysis indicated a metabolic shift towards aerobic glycolysis in sPCL as well as marked down-regulation of enzymes involved in glycan synthesis, potentially mediating altered glycosylation of surface receptors. There was no significant change in overall genomic 5-methylcytosine or 5-hydroxymethylcytosine at the two stages, indicating that epigenetic dysregulation was not a major driver of transformation to sPCL. The present study constitutes the first attempt to provide a comprehensive map of the altered protein expression profile accompanying transformation of MM to sPCL in a single patient, identifying several candidate proteins that can be targeted by currently available small molecule drugs. Our dataset furthermore constitutes a reference dataset for further proteomic analysis of sPCL transformation.