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

Mirabella F, Wu P, Wardell CP, Kaiser MF, Walker BA, Johnson DC, Morgan GJ - Blood Cancer J (2013)

View Article: PubMed Central - PubMed

Affiliation: Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, London, UK.

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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 group, on the basis of experiments showing that t(4;14) cell lines knocked out for MMSET, either on the translocated allele (TKO) or on the non-translocated allele (NTKO), have lower ACA11 levels compared wih their parental cell line (KMS11) with a normal overexpressed MMSET, suggested that ACA11, rather than MMSET, is the key pathogenic gene in t(4;14) MM... In previous studies, the same TKO model system had been used to prove the oncogenic effect of MMSET in myeloma; however, 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... However, when we examined these results in detail, some of the results do not seem to accurately reflect what is understood about the TKO cell line system biology... In order to reconcile the observations reported in the paper with what we understand about the biology of MMSET and other human intronic snoRNAs, we would have to hypothesize that ACA11 biogenesis in myeloma is different... Statistical analysis showed that there is a good correlation between the expression of both genes (Figure 2a), suggesting that their regulation is interdependent... A similar result was found by an independent study recently... To confirm and better characterize this result, we designed and used a qRT-PCR test and applied it to total RNA from KMS11, TKO and NTKO looking at the expression of ACA11 and MMSET... However, in contrast, we could not demonstrate a difference in MMSET mRNA in TKO, KMS11 and NTKO lines, even if these lines have different level of MMSET protein... Taking the RNA-seq and qRT-PCR data as whole, they show that ACA11 expression directly mirrors MMSET expression level, highlighting the correlation demonstrated in primary patient material (Figure 2a)... We also show that ACA11 expression is neither deregulated in the TKO nor in the NTKO cell line compared with parental KMS11... Overall, the data presented here are consistent with MMSET being the key pathologic mediator in t(4;14) myeloma... We do, however, think that ACA11 has an important role in t(4;14) pathogenesis, because evolutionary pressure seems to have kept ACA11 inside the MMSET locus, and often, intronic RNA are found to be involved in the same biochemical pathway as their host gene.

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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.
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fig1: 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.

Mentions: 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.


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

Mirabella F, Wu P, Wardell CP, Kaiser MF, Walker BA, Johnson DC, Morgan GJ - Blood Cancer J (2013)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3674460&req=5

fig1: 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.
Mentions: 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.

View Article: PubMed Central - PubMed

Affiliation: Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, London, UK.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

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 group, on the basis of experiments showing that t(4;14) cell lines knocked out for MMSET, either on the translocated allele (TKO) or on the non-translocated allele (NTKO), have lower ACA11 levels compared wih their parental cell line (KMS11) with a normal overexpressed MMSET, suggested that ACA11, rather than MMSET, is the key pathogenic gene in t(4;14) MM... In previous studies, the same TKO model system had been used to prove the oncogenic effect of MMSET in myeloma; however, 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... However, when we examined these results in detail, some of the results do not seem to accurately reflect what is understood about the TKO cell line system biology... In order to reconcile the observations reported in the paper with what we understand about the biology of MMSET and other human intronic snoRNAs, we would have to hypothesize that ACA11 biogenesis in myeloma is different... Statistical analysis showed that there is a good correlation between the expression of both genes (Figure 2a), suggesting that their regulation is interdependent... A similar result was found by an independent study recently... To confirm and better characterize this result, we designed and used a qRT-PCR test and applied it to total RNA from KMS11, TKO and NTKO looking at the expression of ACA11 and MMSET... However, in contrast, we could not demonstrate a difference in MMSET mRNA in TKO, KMS11 and NTKO lines, even if these lines have different level of MMSET protein... Taking the RNA-seq and qRT-PCR data as whole, they show that ACA11 expression directly mirrors MMSET expression level, highlighting the correlation demonstrated in primary patient material (Figure 2a)... We also show that ACA11 expression is neither deregulated in the TKO nor in the NTKO cell line compared with parental KMS11... Overall, the data presented here are consistent with MMSET being the key pathologic mediator in t(4;14) myeloma... We do, however, think that ACA11 has an important role in t(4;14) pathogenesis, because evolutionary pressure seems to have kept ACA11 inside the MMSET locus, and often, intronic RNA are found to be involved in the same biochemical pathway as their host gene.

No MeSH data available.