Identification of ID-1 as a potential target gene of MMSET in multiple myeloma.
The frequently detected t(4;14)(p16.3;q32) translocation in multiple myeloma (MM) results in a dysregulation of two potential oncogenes: multiple myeloma SET domain (MMSET) and fibroblast growth factor receptor 3 (FGFR3). As the expression of FGFR3 is undetectable in 30% of the t(4;14)+ MM patients, MMSET has been suggested to play an important role in the malignant transformation associated with the t(4;14) translocation. Screening with a real-time polymerase chain reaction (PCR) found complex expression patterns of the MMSET transcripts in fluorescence-activated cell sorted (FACS)-purified plasma cells (PCs) from 15 t(4;14)+ MM patients. In addition, potential target genes of MMSET type I and II were identified, using microarray analyses of MMSET transfected cell lines. Subsequently, the expression of potential target genes was verified by real-time PCR in FACS-purified PCs from 15 t(4;14)+ and 22 t(4;14)- MM patients. We suggest that the inhibitor of differentiation 1 (ID-1) is a target gene of MMSET, based on its upregulation in MMSET transfected cell lines and a significant association between the t(4;14) translocation and ID-1 expression in MM patients (P = 0.002). As high levels of ID-1 are associated with cancer, our findings indicate that MMSET promotes oncogenic transformation in t(4;14)+ MM patients by transcriptional activation of ID-1 expression.
Hudlebusch
Heidi Rye
HR
The Department of Haematology L, Herlev University Hospital, University of Copenhagen, Herlev, Denmark.
Theilgaard-Mönch
Kim
K
Lodahl
Marianne
M
Johnsen
Hans Erik
HE
Rasmussen
Thomas
T
D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D002883:Chromosomes, Human, Pair 14; D002894:Chromosomes, Human, Pair 4; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018390:Gene Targeting; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1; D009101:Multiple Myeloma / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010950:Plasma Cells / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D014162:Transfection; D014178:Translocation, Genetic
D002352:Carrier Proteins; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D012097:Repressor Proteins; D014157:Transcription Factors; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human