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

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.

Sabotaging of the oxidative stress response by an oncogenic noncoding RNA

“…Multiple myeloma (MM) is a malignancy of bone marrow plasma B cells (1), and despite extensive study, its etiology remains unclear. The t(4;14)(p16.3:q32.3) chromosomal translocation is detected in ;20% of MM cases and is associated with a worse prognosis (1,2). The t(4;14) translocation transposes the immunoglobulin heavy chain region enhancer on chromosome 4 and the Wolf-Hirschhorn syndrome candidate 1 (WHSC1), multiple myeloma set domain (MMSET) gene on chromosome 14 (2), resulting in the ectopic overexpression of the WHSC1 and FGFR3 genes.…”

“…The t(4;14)(p16.3:q32.3) chromosomal translocation is detected in ;20% of MM cases and is associated with a worse prognosis (1,2). The t(4;14) translocation transposes the immunoglobulin heavy chain region enhancer on chromosome 4 and the Wolf-Hirschhorn syndrome candidate 1 (WHSC1), multiple myeloma set domain (MMSET) gene on chromosome 14 (2), resulting in the ectopic overexpression of the WHSC1 and FGFR3 genes. Where FGFR3 is deleted in a subset of t(4;14) cases that still have a poor prognosis (3), all cases of t(4;14) myeloma overexpress the MMSET gene, which encodes a H3K36 histone methyltransferase.…”

Identification of ID‐1 as a potential target gene of MMSET in multiple myeloma

“…MMSET is a 90 kb gene with 24 exons having a complex expression pattern caused by alternative splicing and differential polyadenylation (Chesi et al, 1998). The MMSET mRNA isotypes include MMSET type I encoding a shorter protein (647 aa) and MMSET type II encoding a longer protein (1365 aa) ( Fig 1B).…”

“…Recently, a third mRNA isotype (RE-IIBP) has been found that encodes a 584 aa protein identical to the carboxy-teminal region of MMSET type II (Garlisi et al, 2001) ( Fig 1B). MMSET is highly expressed in testis and thymus in adult tissues and to a high degree in embryonic tissues, especially those undergoing rapid proliferation (Chesi et al, 1998). However, the MMSET proteins remain to be identified.…”

“…The biological role of MMSET in MM remains to be investigated. Several conserved domains are located in the amino-terminal region of both MMSET type I and II including a nuclear localisation signal (NLS), a high mobility group box (HMG) domain, and a region homologous to the amino terminus of the hepatoma-derived growth factor (hath), suggesting that MMSET encodes a DNA binding protein capable of protein-protein interactions (Chesi et al, 1998) ( Fig 1B). Furthermore, in the carboxy-terminal region MMSET type II contains a SET domain, a SET-associated cysteine rich (SAC) domain and five plant homeo domain (PHD) zinc fingers ( Fig 1B) which are characteristics of the transcriptional regulators of the TRX group of genes (Chesi et al, 2000;Angrand et al, 2001), which are believed to be involved in transcriptional regulation of gene expression through chromatin remodelling (Chesi et al, 2000).…”