Overexpression of transcripts originating from the MMSET locus characterizes all t(4;14)(p16;q32)-positive multiple myeloma patients

Keats, Jonathan J.; Maxwell, Christopher A.; Taylor, Brian J.; Hendzel, Michael J.; Chesi, Marta; Bergsagel, P. Leif; Larratt, Loree; Mant, Michael J.; Reiman, Tony; Belch, Andrew R.; Pilarski, Linda M.

doi:10.1182/blood-2004-09-3704

Cited by 164 publications

(176 citation statements)

References 45 publications

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“…The NSD family of proteins is essential in development and is mutated in human acute myeloid leukemia, Sotos syndrome, multiple myeloma, and lung cancer (14,26,39,47,49). The SET domain of NSD proteins is homologous to the Saccharomyces cerevisiae histone-3 lysine-36 (H3K36)-specific methyltransferase SET2 and is specific for H3K36 dimethylation (H3K36me2) (30).…”

Section: Proteomic Analysis Of the Brd4-associated Cellular Proteinsmentioning

confidence: 99%

The Brd4 Extraterminal Domain Confers Transcription Activation Independent of pTEFb by Recruiting Multiple Proteins, Including NSD3

Rahman

Sowa

Ottinger

et al. 2011

Molecular and Cellular Biology

475

490

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Bromodomain protein 4 (Brd4) plays critical roles in development, cancer progression, and virus-host pathogenesis. To gain mechanistic insight into the various biological functions of Brd4, we performed a proteomic analysis to identify and characterize Brd4-associated cellular proteins. We found that the extraterminal (ET) domain, whose function has to date not been determined, interacts with NSD3, JMJD6, CHD4, GLTSCR1, and ATAD5. These ET-domain interactions were also conserved for Brd2 and Brd3, the other human BET proteins tested. We demonstrated that GLTSCR1, NSD3, and JMJD6 impart a pTEFb-independent transcriptional activation function on Brd4. NSD3 as well as JMJD6 is recruited to regulated genes in a Brd4-dependent manner. Moreover, we found that depletion of Brd4 or NSD3 reduces H3K36 methylation, demonstrating that the Brd4/NSD3 complex regulates this specific histone modification. Our results indicate that the Brd4 ET domain through the recruitment of the specific effectors regulates transcriptional activity. In particular, we show that one of these effectors, NSD3, regulates transcription by modifying the chromatin microenvironment at Brd4 target genes. Our study thus identifies the ET domain as a second important transcriptional regulatory domain for Brd4 in addition to the carboxyl-terminal domain (CTD) that interacts with pTEFb.One mechanism underlying the regulation of gene expression is the targeting of multiprotein complexes to modified histones, which then alters the chromatin microenvironment to stimulate or inhibit gene expression. The bromodomains and extraterminal (BET) domain family of proteins are characterized by the presence of two conserved domains, the tandem, amino-terminal bromodomains (BDI and BDII), which bind acetylated chromatin, and an extraterminal (ET) domain, whose function is unknown. The BET family is conserved from yeast to mammals and includes Saccharomyces cerevisiae bromodomain factor 1 (bdf1) and bromodomain factor 2 (bdf2), Drosophila melanogaster female sterile homeotic [fs(1)h], and mammalian Brd2, Brd3, Brd4, and testes/oocyte-specific BrdT/ Brd6. In yeast, deletion of bdf1 leads to a reduced growth rate and deletion of both bdf1 and bdf2 is lethal (27). Mutations of fs(1)h cause segmental abnormalities, including missing organs and homeotic transformations in the progeny of mutant females in Drosophila (13). Knockout of Brd4 or Brd2 in mice results in early embryonic lethality (18,21).The BET proteins have been shown to be important players in human disease, including viral infections and cancer. Several different viruses target the individual BET proteins for a variety of purposes but often to regulate viral and cellular transcription (4,7,31,37,41,45,57,60). The papillomavirus E2 proteins bind to Brd4, and some utilize this interaction in tethering the viral genomes to mitotic chromosomes (1,3,57,59). The papillomavirus E2 transcriptional activation functions are also mediated through Brd4 (35,41,42). With regard to human cancer, the Brd4-NUT and Brd3-NUT fusio...

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Section: Proteomic Analysis Of the Brd4-associated Cellular Proteinsmentioning

confidence: 99%

The Brd4 Extraterminal Domain Confers Transcription Activation Independent of pTEFb by Recruiting Multiple Proteins, Including NSD3

Rahman

Sowa

Ottinger

et al. 2011

Molecular and Cellular Biology

475

490

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“…5 We therefore depleted MMSET and found decreased survival in 2 cell lines of the MS subgroup ( Figure 2A). The MMSET shRNA targets both the short and long isoforms of MMSET (MMSET I and MMSET II 16 ), but not REIIBP, another transcript from this genomic locus. This MMSET shRNA construct has been further validated by others.…”

Section: Mmset Regulates Maf Transcriptionmentioning

confidence: 99%

A mechanistic rationale for MEK inhibitor therapy in myeloma based on blockade of MAF oncogene expression

Annunziata

Hernandez²,

Davis

et al. 2011

Blood

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Modulating aberrant transcription of oncogenes is a relatively unexplored opportunity in cancer therapeutics. In approximately 10% of multiple myelomas, the initiating oncogenic event is translocation of musculoaponeurotic fibrosarcoma oncogene homolog (MAF), a transcriptional activator of key target genes, including cyclinD2. Our prior work showed that MAF is up-regulated in an additional 30% of multiple myeloma cases. The present study describes a common mechanism inducing MAF transcription in both instances. The IntroductionMultiple myeloma (MM) is a malignancy of plasma cells that is diagnosed in 20 000 people annually in the United States. 1 Current therapy includes high-dose chemotherapy in conjunction with bone marrow transplantation as well as newer agents, such as bortezomib and lenalidomide. 2 Although these treatments extend survival, they often do not achieve lasting cures, providing an impetus to search for novel therapeutic modalities.MM is molecularly heterogeneous, with 7 subgroups defined by gene expression profiling. 3 Four of these subgroups were associated with recurrent translocations in which an oncogene (musculoaponeurotic fibrosarcoma oncogene homolog [MAF]/MAFB, multiple myeloma SET domain [MMSET]/FGFR3, Cyclin D1 or Cyclin D3) is juxtaposed to immunoglobulin heavy chain (IgH) enhancer elements, causing aberrant oncogene expression. Of the 7 subgroups, the MMSET/FGFR3 and MAF subgroups have been associated with inferior overall survival. 3 MAF is a B-ZIP transcription factor that is aberrantly expressed in myeloma by 2 distinct molecular mechanisms. 4 Approximately 10% of primary myelomas bear a MAF translocation that is associated with very high MAF expression. Typically, the MAF translocation breakpoint occurs many kilobases upstream of the MAF transcriptional start site, suggesting that the IgH enhancer elements drive transcription by regulatory elements in the normal MAF promoter. Other myeloma cases lack an MAF translocation but nonetheless express MAF at levels above those in normal plasma cells. 5 In myeloma cell lines overexpressing MAF by either mechanism, interference with MAF function blocked cell proliferation. 5 This essential function of MAF is probably the result, in part, of its transactivation of cyclin D2, a key regulator of the G 1 -S phase transition of the cell cycle. In addition, MAF expression in myeloma cells causes them to adhere more avidly to bone marrow stromal cells, leading to greater vascular endothelial growth factor secretion by stromal cells; transactivation of integrin ␤7 by MAF contributes to these microenvironmental phenotypes. 5 Furthermore, MAF may regulate invasion and metastasis of cancer cells through its activation of the AKT pathway. 4 These studies established MAF as a target for therapeutic intervention in MM but did not provide a ready means to achieve this clinically. In the present study, we hypothesized that MAF transcription might be driven by intracellular signal transduction pathways, downstream of MMSET, that could be inhibited by ...

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“…Loss of a nucleolar exclusion signal at the amino terminus of WHSC1-II causes altered subcellular localization of these shortened WHSC1 protein products (21), and Ser 102 is lost in these truncations, affecting function of WHSC1 in DNA repair (9). Yet, the clinical course of t(4;14)-positive patients is independent of the location of the translocation breakpoints within WHSC1 (21). Therefore, the precise mechanism by which these different WHSC1 gene products contribute to transformation remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Multiple myeloma–associated chromosomal translocation activates orphan snoRNA ACA11 to suppress oxidative stress

Chu

Su²,

Maggi³

et al. 2012

J. Clin. Invest.

135

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Overexpression of transcripts originating from the MMSET locus characterizes all t(4;14)(p16;q32)-positive multiple myeloma patients

Cited by 164 publications

References 45 publications

The Brd4 Extraterminal Domain Confers Transcription Activation Independent of pTEFb by Recruiting Multiple Proteins, Including NSD3

The Brd4 Extraterminal Domain Confers Transcription Activation Independent of pTEFb by Recruiting Multiple Proteins, Including NSD3

A mechanistic rationale for MEK inhibitor therapy in myeloma based on blockade of MAF oncogene expression

Multiple myeloma–associated chromosomal translocation activates orphan snoRNA ACA11 to suppress oxidative stress

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