title: Frequent PVT1 rearrangement and novel chimeric genes PVT1-NBEA and PVT1-WWOX occur in multiple myeloma with 8q24 abnormality.
abstract: Chromosome 8q24 rearrangements are occasionally found in multiple myeloma and are associated with tumor progression. The 8q24 rearrangements were detected by FISH in 12 of 54 patients with multiple myeloma (22.2%) and in 8 of 11 multiple myeloma cell lines (72.7%). The breakpoints of 8q24 in 10 patients with multiple myeloma and in all multiple myeloma cell lines were assigned to a 360 kb segment, which was divided into 4 regions: approximately 120 kb centromeric to MYC (5' side of MYC), the region centromerically adjacent to PVT1 (~ 170 kb region, including MYC, of 5' side of PVT1), the PVT1 region, and the telomeric region to PVT1. PVT1 rearrangements were most common and found in 7 of 12 patients (58.3%) and 5 of 8 cell lines (62.5%) with 8q24 abnormalities. A combination of spectral karyotyping (SKY), FISH, and oligonucleotide array identified several partner loci of PVT1 rearrangements, such as 4p16, 4q13, 13q13, 14q32, and 16q23-24. Two novel chimeric genes were identified: PVT1-NBEA in the AMU-MM1 cell line harboring t(8;13)(q24;q13) and PVT1-WWOX in RPMI8226 cell line harboring der(16)t(16;22)ins(16;8)(q23;q24). The PVT1-NBEA chimera in which PVT1 exon 1 was fused to NBEA exon 2 and the PVT1-WWOX in which PVT1 exon 1 was fused to WWOX exon 9 were associated with the expression of abnormal NBEA and WWOX lacking their N-terminus, respectively. These findings suggest that PVT1 rearrangements may represent a novel molecular paradigm underlying the pathology of 8q24 rearrangement-positive multiple myeloma.
authors.affiliation: Department of Hematology and Oncology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Nagoshi
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Taki
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hanamura
authors.forename: Masakazu
authors.initials: M
authors.lastname: Nitta
authors.forename: Takemi
authors.initials: T
authors.lastname: Otsuki
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nishida
authors.forename: Keiko
authors.initials: K
authors.lastname: Okuda
authors.forename: Natsumi
authors.initials: N
authors.lastname: Sakamoto
authors.forename: Satoru
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Mio
authors.initials: M
authors.lastname: Yamamoto-Sugitani
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tsutsumi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Shigeo
authors.initials: S
authors.lastname: Horiike
authors.forename: Junya
authors.initials: J
authors.lastname: Kuroda
authors.forename: Masafumi
authors.initials: M
authors.lastname: Taniwaki
mesh_terms: D002352:Carrier Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D046228:Microarray Analysis / Q000379:methods; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010088:Oxidoreductases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D034622:RNA Interference; D062085:RNA, Long Noncoding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D032681:Spectral Karyotyping; D025521:Tumor Suppressor Proteins / Q000235:genetics; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D002352:Carrier Proteins; C498595:NBEA protein, human; D009419:Nerve Tissue Proteins; D015514:Oncogene Proteins, Fusion; C521123:PVT1 long-non-coding RNA, human; C576954:PVT1-NBEA fusion protein, human; C576955:PVT1-WWOX fusion protein, human; D011506:Proteins; D062085:RNA, Long Noncoding; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human