The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts.
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).
Chesi
M
M
Department of Medicine, the Division of Hematology and Oncology, Weill Medical College of Cornell University, New York, NY, USA.
Nardini
E
E
Lim
R S
RS
Smith
K D
KD
Kuehl
W M
WM
Bergsagel
P L
PL
D000595:Amino Acid Sequence; D002352:Carrier Proteins; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics* / Q000648:ultrastructure; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics* / Q000648:ultrastructure; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000235:genetics; D005091:Exons / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005803:Genes, Immunoglobulin; D006609:High Mobility Group Proteins / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007621:Karyotyping; D008297:Male; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics*; D011061:Poly A / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases; D012326:RNA Splicing; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D012097:Repressor Proteins; D013737:Testis / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D017931:DNA Primers; D004273:DNA, Neoplasm; D006609:High Mobility Group Proteins; C115494:IgH-MMSET fusion protein, human; D007143:Immunoglobulin Heavy Chains; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D017468:Receptors, Fibroblast Growth Factor; D012097:Repressor Proteins; D011061:Poly A; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human; C496365:FGFR3 protein, human; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3