The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts

Blood. 1998 Nov 1;92(9):3025-34.

Abstract

Previously we reported that a karyotypically silent t(4;14)(p16. 3;q32.3) translocation is present in about 25% of multiple myeloma (MM) tumors, and causes overexpression of FGFR3, which is 50 to 100 kb telomeric to the 4p16 breakpoints. Frequent FGFR3 kinase activating mutations in MM with t(4;14) translocations substantiate an oncogenic role for FGFR3. We now report that the 4p16 breakpoints occur telomeric to and within the 5' introns of a novel gene, MMSET (Multiple Myeloma SET domain). In normal tissues, MMSET has a complex pattern of expression with a short form (647 amino acids [aa]) containing an HMG box and hath region, and an alternatively spliced long form (1365 aa) containing the HMG box and hath region plus 4 PHD fingers and a SET domain. Although t(4;14) translocation results in IgH/MMSET hybrid transcripts, overexpression of MMSET also occurs from endogenous promoters on 4p16. Given the homology to HRX/MLL1/ALL1 at 11q23 that is dysregulated by translocations in acute leukemia, we hypothesize that dysregulation of MMSET contributes to neoplastic transformation in MM with t(4;14) translocation. This is the first example of an IgH translocation that simultaneously dysregulates two genes with oncogenic potential: FGFR3 on der(14) and MMSET on der(4).

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Carrier Proteins*
  • Cell Transformation, Neoplastic / genetics*
  • Chromosomes, Human, Pair 14 / genetics*
  • Chromosomes, Human, Pair 14 / ultrastructure
  • Chromosomes, Human, Pair 4 / genetics*
  • Chromosomes, Human, Pair 4 / ultrastructure
  • DNA Primers
  • DNA, Neoplasm / genetics
  • Exons / genetics
  • Gene Expression Regulation, Neoplastic
  • Genes, Immunoglobulin*
  • High Mobility Group Proteins / genetics*
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Immunoglobulin Heavy Chains / genetics*
  • Karyotyping
  • Male
  • Molecular Sequence Data
  • Multiple Myeloma / genetics*
  • Multiple Myeloma / pathology
  • Oncogene Proteins, Fusion / biosynthesis
  • Oncogene Proteins, Fusion / genetics*
  • Poly A / metabolism
  • Promoter Regions, Genetic
  • Protein-Tyrosine Kinases*
  • RNA Splicing
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • RNA, Neoplasm / biosynthesis
  • RNA, Neoplasm / genetics
  • Receptor, Fibroblast Growth Factor, Type 3
  • Receptors, Fibroblast Growth Factor / genetics*
  • Repressor Proteins*
  • Testis / metabolism
  • Thymus Gland / metabolism
  • Translocation, Genetic*
  • Tumor Cells, Cultured

Substances

  • Carrier Proteins
  • DNA Primers
  • DNA, Neoplasm
  • High Mobility Group Proteins
  • IgH-MMSET fusion protein, human
  • Immunoglobulin Heavy Chains
  • Oncogene Proteins, Fusion
  • RNA, Messenger
  • RNA, Neoplasm
  • Receptors, Fibroblast Growth Factor
  • Repressor Proteins
  • Poly A
  • Histone-Lysine N-Methyltransferase
  • NSD2 protein, human
  • FGFR3 protein, human
  • Protein-Tyrosine Kinases
  • Receptor, Fibroblast Growth Factor, Type 3

Associated data

  • GENBANK/AF071593
  • GENBANK/AF071594
  • GENBANK/AF071595