The t(4;14) Translocation in Myeloma Dysregulates Both FGFR3and a Novel Gene, MMSET, Resulting in IgH/MMSET Hybrid Transcripts

Author:

Chesi Marta1,Nardini Elena1,Lim Robert S.C.1,Smith Kerrington D.1,Kuehl W. Michael1,Bergsagel P. Leif1

Affiliation:

1. From the Department of Medicine, the Division of Hematology and Oncology, Weill Medical College of Cornell University, New York, NY; and the Genetics Department, Medicine Branch, National Cancer Institute, Bethesda, MD.

Abstract

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 SETdomain). In normal tissues, MMSET has a complex pattern of expression with a short form (647 amino acids [aa]) containing an HMG box andhath 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/ALL1at 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) andMMSET on der(4). © 1998 by The American Society of Hematology.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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