title: Genomic characterization of the chromosomal breakpoints of t(4;14) of multiple myeloma suggests more than one possible aetiological mechanism.
abstract: Using FISH-based techniques, rearrangements of the immunoglobulin heavy-chain (IgH) locus at 14q32 have been found in the majority of cases of multiple myeloma (MM). Some of these IgH translocations are recurrent and we have characterized the genomic breakpoints of seven t(4;14) translocations from MM patients, using a combination of vectorette and conventional polymerase chain reaction methods, the aim being to understand the molecular mechanism leading to MM. Conventionally, the chromosome 14q32 breakpoints in these reciprocal translocations are believed to be located in the IgH mu switch (S) region and a further downstream S region with deletion of intervening DNA occurring as a result of aberrant class switch recombination (CSR); this was seen in five of the cases analysed. However, in two patients it was possible to demonstrate that the rearranged hybrid switch region sequence was joined to DNA from chromosome 4p16, suggesting that IgH translocations can occur in B cells that have already undergone legitimate CSR. The complex nature of these rearrangements leads us to speculate that primary IgH translocations may occur at different time points in the development in MM plasma cells, either at the time of physiological CSR or at a later stage, possibly involving a different mechanism.
authors.affiliation: Academic Unit of Haematology and Oncology, Algernon Firth Building, University of Leeds, LEEDS LS2 9JT, UK. jamesf@lrf.leeds.ac.uk
authors.forename: James A L
authors.initials: JA
authors.lastname: Fenton
authors.forename: Guy
authors.initials: G
authors.lastname: Pratt
authors.forename: Andy C
authors.initials: AC
authors.lastname: Rawstron
authors.forename: Kathryn
authors.initials: K
authors.lastname: Sibley
authors.forename: Dominic
authors.initials: D
authors.lastname: Rothwell
authors.forename: Zoe
authors.initials: Z
authors.lastname: Yates
authors.forename: Ann
authors.initials: A
authors.lastname: Dring
authors.forename: Steve J
authors.initials: SJ
authors.lastname: Richards
authors.forename: A John
authors.initials: AJ
authors.lastname: Ashcroft
authors.forename: Faith E
authors.initials: FE
authors.lastname: Davies
authors.forename: Roger G
authors.initials: RG
authors.lastname: Owen
authors.forename: J Anthony
authors.initials: JA
authors.lastname: Child
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Morgan
mesh_terms: D001402:B-Lymphocytes / Q000473:pathology; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D019457:Chromosome Breakage; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics* / Q000648:ultrastructure; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics* / Q000648:ultrastructure; D002999:Clone Cells / Q000473:pathology; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D005803:Genes, Immunoglobulin; D005812:Genes, Switch; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics; D007134:Immunoglobulin Switch Region / Q000235:genetics; D007148:Immunoglobulin mu-Chains / Q000235:genetics; D008954:Models, Biological; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000209:etiology / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000473:pathology; D016133:Polymerase Chain Reaction / Q000379:methods; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D014178:Translocation, Genetic / Q000235:genetics*
chemical_list: D007148:Immunoglobulin mu-Chains