title: Plasma membrane proteomics identifies biomarkers associated with MMSET overexpression in T(4;14) multiple myeloma.
abstract: Multiple myeloma (MM) is characterized by recurrent chromosomal translocations. MMSET, identified by its fusion to the IgH locus in t(4;14) MM, is universally overexpressed in t(4;14) MM. In order to identify cell surface biomarkers associated with t(4;14) MM for small molecule or antibody based therapies, we knocked down MMSET expression with shRNA and generated a cell line pair from KMS11, a t(4;14) MM cell line. We used quantitative mass spectrometry to identify plasma membrane proteins associated with MMSET overexpression. Using this approach, 50 cell surface proteins were identified as differentially expressed between KMS11 and KMS11/shMMSET. Western blot and flow cytometry analysis indicated SLAMF7 was over-expressed in t(4;14) MM cell lines and down-regulated by MMSET shRNAs. SLAMF7 expression was also confirmed in primary t(4;14) MM samples by flow cytometry analysis. Quantitative RT-PCR and ChIP analysis indicated MMSET might regulate the transcription level of SLAMF7 and be an important functional element for SLAMF7 promoter activity. Furthermore, SLAMF7 shRNA could induce G1 arrest or apoptosis and reduce clonogenetic capacity in t(4;14) MM cells. Overall, these results illustrated SLAMF7 might be a novel cell surface protein associated with t(4;14) MM. It is potential to develop t(4;14) MM targeted therapy by SLAMF7 antibody mediated drug delivery.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Xie
authors.forename: Jayantha
authors.initials: J
authors.lastname: Gunaratne
authors.forename: Lip Lee
authors.initials: LL
authors.lastname: Cheong
authors.forename: Shaw Cheng
authors.initials: SC
authors.lastname: Liu
authors.forename: Tze Loong
authors.initials: TL
authors.lastname: Koh
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Huang
authors.forename: Walter P
authors.initials: WP
authors.lastname: Blackstock
authors.forename: Wee Joo
authors.initials: WJ
authors.lastname: Chng
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D002883:Chromosomes, Human, Pair 14; D002894:Chromosomes, Human, Pair 4; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000071176:Signaling Lymphocytic Activation Molecule Family; D014162:Transfection; D014178:Translocation, Genetic
chemical_list: D014408:Biomarkers, Tumor; D011971:Receptors, Immunologic; D012097:Repressor Proteins; C448987:SLAMF7 protein, human; D000071176:Signaling Lymphocytic Activation Molecule Family; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human
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