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

M Chesi, E Nardini, RSC Lim, KD Smith… - Blood, The Journal …, 1998 - ashpublications.org
M Chesi, E Nardini, RSC Lim, KD Smith, WM Kuehl, PL Bergsagel
Blood, The Journal of the American Society of Hematology, 1998ashpublications.org
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 (M ultiple M yeloma SET domain). In normal tissues …
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.
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