Work

MMSET is the key molecular target in t(4;14) myeloma

Year: 2013

Type: article

Abstract: The t(4;14)(p16.3;q32.3) is found in 15% of presenting multiple myeloma (MM) cases and is associated with a significantly worse prognosis than other biological subgroups. As a consequence of the translocation, two genes are aberrantly expressed, the fibroblast growth factor receptor 3 ( FGFR3 ) and a multiple myeloma SET domain containing protein, MMSET ( WHSC1/NSD2 ), both of which have potential oncogenic activity. 1 Importantly, FGFR3 shows only weak transforming activity and is eventually lost in 30% of patients, 2 suggesting that it is not the main oncogenic factor. In contrast, MMSET gene overexpression is universal, and when it is knocked down experimentally, there is inhibition of proliferation, induction of apoptosis and alteration of cell adhesion, 3 , 4 , 5 suggesting it is central to the pathogenesis of this subtype of MM. MMSET is known to have histone methyl transferase activity 6 and is deregulated early on in the genesis of developing myeloma, and could therefore constitute a good therapeutic target. The MMSET locus in t(4;14) myeloma patients has a complicated genomic structure and after translocation events and RNA splicing, a number of different transcripts are generated ( Figure 1 ). This genetic complexity of MMSET has been added to recently by the discovery of the H/ACA box RNA ACA11 ( SCARNA22 ), that has been found within intron 20 of MMSET and is also overexpressed in the t(4;14) subgroup. 7 This small RNA has been suggested to be key to the pathogenesis of t(4;14) MM, raising the question that it may constitute the main therapeutic target. Figure 1 MMSET genetic map on chromosome 4. The position of the different translocation events in MM is shown by slashed lines. Gray and black ovals indicate non-coding and coding exons, respectively; dotted straight line between exons represent the introns. Splicing event for the canonical longest MMSET isoform is shown by joining lines between exons. Exons 4a and 11, shown by white triangles, are used only for alternative splicing and are not present in the longest MMSET isoform. Exon 7, deleted in TKO and NTKO lines, is indicated by a white star. Transcription start sites and first translated codons (ATG) for MMSET and REIIBP are indicated, respectively, by bent black arrows and open arrows. Genomic position for ACA11 is shown by a white arrow. Full size image

Source: Blood Cancer Journal

DOI: 10.1038/bcj.2013.9