Characterization of oncogene dysregulation in multiple myeloma by combined FISH and DNA microarray analyses.
Chromosomal translocations involving the immunoglobulin heavy chain (IGH) locus and various partner loci frequently are associated with multiple myeloma (MM). We investigated the expression profiles of the FGFR3/MMSET, CCND1, CCND3, MAF, and MAFB genes, which are involved in t(4;14)(p16.3;q32), t(11;14)(q13;q32), t(6;14)(p21;q32), t(14;16)(q32;q23), and t(14;20)(q32;q12), respectively, in purified plasma cell populations from 39 MMs and six plasma cell leukemias (PCL) by DNA microarray analysis and compared the results with the presence of translocations as assessed by dual-color FISH or RT-PCR. A t(4;14) was found in 6 MMs, t(11;14) in 9 MMs and 1 PCL, t(6;14) in 1 MM, t(14;16) in 2 MMs and 1 PCL, and t(14;20) in 1 PCL. In all cases, the translocations were associated with the spiked expression of target genes. Furthermore, gene expression profiling enabled the identification of putative translocations causing dysregulation of CCND1 (1 MM and 1 PCL) and MAFB (1 MM and 1 PCL) without any apparent involvement of immunoglobulin loci. Notably, all of the translocations were mutually exclusive. Markedly increased MMSET expression was found in 1 MM showing associated FGFR3 and MMSET signals on an unidentified chromosome. Our data suggest the importance of using combined molecular cytogenetic and gene expression approaches to detect genetic aberrations in MM.
Fabris
Sonia
S
Laboratorio di Ematologia Sperimentale e Genetica Molecolare, UO Ematologia 1, Dipartimento di Scienze Mediche, Università degli Studi di Milano, Ospedale Maggiore IRCCS, Milan, Italy.
Agnelli
Luca
L
Mattioli
Michela
M
Baldini
Luca
L
Ronchetti
Domenica
D
Morabito
Fortunato
F
Verdelli
Donata
D
Nobili
Lucia
L
Intini
Daniela
D
Callea
Vincenzo
V
Stelitano
Caterina
C
Lombardi
Luigia
L
Neri
Antonino
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics; D056743:Cyclin D3; D016213:Cyclins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods*; D016215:Macrophage-Activating Factors / Q000235:genetics; D051258:MafB Transcription Factor; D008297:Male; D046228:Microarray Analysis / Q000379:methods*; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion; D009857:Oncogenes / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014178:Translocation, Genetic / Q000235:genetics
C534696:CCND3 protein, human; D002352:Carrier Proteins; D056743:Cyclin D3; D016213:Cyclins; D004268:DNA-Binding Proteins; C490407:MAFB protein, human; D016215:Macrophage-Activating Factors; D051258:MafB Transcription Factor; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D017468:Receptors, Fibroblast Growth Factor; D012097:Repressor Proteins; D014157:Transcription Factors; D019938:Cyclin D1; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human; C496365:FGFR3 protein, human; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3