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 activity6 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.
Highlights
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
The same TKO model system had been used to prove the oncogenic effect of MMSET in myeloma;5,6 in these more recent experiments where ACA11 was knocked down, the key implication of the work seemed to shift the pathogenic importance from MMSET to ACA11.7
In order to reconcile the observations reported in the paper with what we understand about the biology of MMSET and other human intronic small nucleolar RNA (snoRNA), we would have to hypothesize that ACA11 biogenesis in myeloma is different
Summary
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. The MMSET gene was erroneously reported to be deleted, whereas, the TKO and NTKO cell lines were generated from the parental KMS11 t(4;14) line, by deleting MMSET exon 7 only5 (Figure 1). Both TKO and NTKO cell lines express the MMSET isoform REIIBP.5 REIIBP mRNA is transcribed from an intronic promoter downstream of both the TKO and NTKO knockout mutation12 (Figure 1), and harbors intron 20, the location of the ACA11 gene.
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