Detection of MUM1/IRF4-IgH fusion in multiple myeloma

Yoshida, Shigeaki; Nakazawa, Naozo; Iida, Shinsuke; Hayami, Yoshihito; Sato, Shigeki; Wakita, Atsushi; Shimizu, S; Taniwaki, Masafumi; Ueda, Ryuzo

doi:10.1038/sj.leu.2401563

Cited by 68 publications

(58 citation statements)

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“…This translocation was identi®ed by metaphase FISH analyses in three of 17 (18%) MM cell lines that were screened (Yoshida et al, 1999). Although IRF-4 is normally expressed in most MM cell lines, the three lines with the translocation expressed much higher levels.…”

Section: P25 ± Mum1/irf-4mentioning

confidence: 99%

Chromosome translocations in multiple myeloma

2001

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Section: P25 ± Mum1/irf-4mentioning

confidence: 99%

Chromosome translocations in multiple myeloma

2001

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“…MUM1 originally gained attention from molecular hematologists because of its involvement in the t(6;14)(p25;q32) translocation of multiple myeloma, which causes the juxtaposition of the MUM1 gene, mapping at 6p25, to the Ig H locus on 14q32. 16,17 Before being discovered as a protooncogene of hematologic neoplasia, though, MUM1 had been extensively investigated by immunologists who defined that MUM1 is a lymphocyte-specific member of the interferon regulatory factor family of transcription factors. 18 Hence, the various names assigned to MUM1, which include IRF4 (for Interferon Regulatory Factor 4), ICSAT (for Interferon Consensus Sequence binding protein for Activated T cells) and Pip (for PU.1 Interaction Partner).…”

mentioning

confidence: 99%

MUM1: a step ahead toward the understanding of lymphoma histogenesis

Gaïdano

Carbone

2000

Leukemia

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Lymphomagenesis is a complex process involving a panoplia of molecular pathways causing transformation of mature lymphoid cells. 1 Each of these pathways is characterized by molecular lesions of cancer related genes and targets a specific stage of lymphoid differentiation 1 (Figure 1). Because each molecular pathway selectively associates with a given clinico-pathologic category of lymphoma, it is assumed that the genetic heterogeneity of lymphoma drives the histological, phenotypical and clinical heterogeneity of these diseases. Research performed during the last decade has been most intense in the field of lymphoma pathogenesis, and has led to the characterization of many cancer-related genes involved in the molecular pathways of lymphoma. 1 Conversely, investigations of lymphoma histogenesis have been lagging behind compared to studies of lymphoma pathogenesis and, therefore, comprehension of the precise cellular counterpart from which a given lymphoma derives is less advanced than knowledge of the genetic lesions associated with the tumor clone.In recent times, however, the field of B cell lymphoma his- (Figure 2). Because these histogenetic markers are also retained upon neoplastic transformation, the origin and differentiation stage of a given lymphoma may be temptatively assigned based on the combination of histogenetic markers associated with the tumor clone ( Figure 2). To date, welldefined histogenetic markers of B cell lymphoma include mutations of immunoglobulin (Ig) and BCL-6 genes, expression of the BCL-6 protein, and, at least in the context of immunodeficiency-related lymphoma, expression of the CD138/syndecan-1 antigen. 2-7 Mutations of Ig genes are accumulated at the time of B cell transit through the germinal center (GC) and are maintained thereafter upon B cell exit from the GC. 2,4 Similarly, recent evidence has shown that normal GC B cells also accumulate mutations of the noncoding regions of the BCL-6 proto-oncogene, which therefore parallel Ig mutations as markers of GC transit. [5][6][7] Because both Ig and BCL-6 mutations are maintained by B cells upon GC exit and further differentiation, they cannot discriminate between GC and post-GC B cells. Such distinction can be eased by phenotypic markers of histogenesis. Available phenotypic markers of histogenesis include expression of the BCL-6 protein, which is restricted to B cells reflecting a GC stage of differentiation, and CD138/syndecan-1, a proteoglycan clustering with late stages of B cell maturation. 3,[8][9][10][11]

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“…8,9,[13][14][15][16][17][18] The ODA cell line was originally established from a female patient with IgG-type MM, but had lost its ability to secrete the M protein as a result of long-term cell culture. G-banding analysis of the ODA cells revealed a complex karyotype featuring near-tetraploidy with two or three der (14) chromosomes.…”

Section: Cell Linesmentioning

confidence: 99%

“…9,13,20 Each PAC/BAC DNA was labeled with either Spectrum Orange or Spectrum Green with the aid of a nick translation kit (Vysis Inc., purchased through Fujisawa Pharmaceutical Co., Osaka, Japan) according to the manufacturer's instructions. DNA derived from YAC clone, Y6, spanning variable region (IgVH), and those of a bacteriophage clone, Igg1-10, or BAC417p24 (BAC/PAC Resources, Oakland, CA, USA) spanning the constant region were used as probes for the IgH gene at the 14q32 locus as previously described.…”

Section: Double Color Fish (Dcfish) Analysismentioning

confidence: 99%

“…Recurrent aberrations include those involving the immunoglobulin heavy (IgH) and light chain (Igk and Igl) gene loci. In particular, 14q+ chromosomes, which represent rearrangements between IgH and various donor chromosomal loci, such as 11q13, 6p25, 4p16, 16q23, 8q24 and 20q11, have been suggested to play crucial roles in MM development due to deregulation of Cyclin D1, 7 MUM1/IRF4, 8,9 FGFR3, 10 c-MAF, 11 c-MYC 12 and MAFB, 13 respectively. In order to characterize the novel chromosomal translocations involved in human MM and to find the relevant proto-oncogene(s)/tumor suppressor gene(s) involved, we isolated the 1p34 breakpoint region of t(1;14)(p34;q32) found in the human MM cell line, ODA.…”

Section: Introductionmentioning

confidence: 99%

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Inactivation of the E3/LAPTm5 gene by chromosomal rearrangement and DNA methylation in human multiple myeloma

et al. 2003

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Chromosomal band 1p34-36 is a commonly rearranged locus in many types of cancers. We cloned the breakpoint region of a chromosomal translocation, t(1;14)(p34;q32), found in the human multiple myeloma (MM) cell line, ODA. This rearrangement occurred between the nearby switch region of the immunoglobulin heavy chain (IgH) gene (Sc3) at 14q32 and the first intron of the human retinoic acid-inducible E3 protein (E3)/lysosomeassociated protein, transmembrane-5 (LAPTm5) gene at the 1p34 locus. Consequently, the E3 gene, which is a hematopoietic cell-specific transcript induced by retinoic acid and located at the rearranged allele, was interrupted within its coding region and was not expressed in the ODA cell line in spite of the other allele still being intact. The expression derived from the remaining intact allele in ODA cells was silenced by DNA methylation at sequences within the first intron around a GC-rich EagI site. Interestingly, the silenced expression of E3 mRNA due to DNA methylation of intron 1 sequences was frequently encountered in MM cells [6/10 (60%) of MM cell lines tested], while E3 is expressed in normal plasma cells and in most other hematopoietic cell lines including those of B-cell lineage. Thus, as the E3 protein has been suggested to be involved in cellular differentiation and apoptotic pathways in certain cell types, our results suggest that loss of E3 gene expression might be a crucial event during the progression of human MM.

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Detection of MUM1/IRF4-IgH fusion in multiple myeloma

Abstract: MUM1 (multiple myeloma oncogene 1)/IRF4 (interferon regulatory factor 4) gene has been identified as an oncogene transcriptionally activated by t(6;14)(p25;q32) chromosomal translocation in multiple myeloma (MM).

Cited by 68 publications

References 4 publications

Chromosome translocations in multiple myeloma

Chromosome translocations in multiple myeloma

MUM1: a step ahead toward the understanding of lymphoma histogenesis

Inactivation of the E3/LAPTm5 gene by chromosomal rearrangement and DNA methylation in human multiple myeloma

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