Correlation of <i>TACC3, FGFR3, MMSET</i> and <i>p21</i> expression with the t(4;14)(p16·3;q32) in multiple myeloma

Stewart, James; Thompson, Alexander; Santra, Madhumita; Barlogie, Bart; Lappin, Terence; Shaughnessy, John D.

doi:10.1111/j.1365-2141.2004.04996.x

Cited by 39 publications

(31 citation statements)

References 14 publications

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“…5). These results were confirmed by immunohistochemical studies of bone marrow biopsy specimens, showing frequent C/T antigen expression among patients with cytogenetic abnormalities and almost universally at relapse (6).…”

Section: Introductionsupporting

confidence: 69%

Protein Transduction of Dendritic Cells for NY-ESO-1-Based Immunotherapy of Myeloma

et al. 2005

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Myeloma vaccines, based on dendritic cells pulsed with idiotype or tumor lysate, have been met with limited success, probably in part due to insufficient cross-priming of myeloma antigens. A powerful method to introduce myeloma-associated antigens into the cytosol of dendritic cells is protein transduction, a process by which proteins fused with a protein transduction domain (PTD) freely traverse membrane barriers. NY-ESO-1, an immunogenic antigen by itself highly expressed in 60% of high-risk myeloma patients, was purified to near homogeneity both alone and as a recombinant fusion protein with a PTD, derived from HIV-Tat. Efficient entry of PTD-NY-ESO-1 into dendritic cells, confirmed by microscopy, Western blotting, and intracellular flow cytometry, was achieved without affecting dendritic cell phenotype. Experiments with amiloride, which inhibits endocytosis, and N-acetyl-L-leucinyl-L-norleucinal, a proteasome inhibitor, confirmed that PTD-NY-ESO-1 entered dendritic cells by protein transduction and was degraded by the proteasome. Tetramer analysis indicated superior generation of HLA-A2.1, CD8 + T lymphocytes specific for NY-ESO-1 157-165 with PTD-NY-ESO-1 compared with NY-ESO-1 control protein (44% versus 2%, respectively). NY-ESO-1-specific T lymphocytes generated with PTD-NY-ESO-1 secreted IFN-; indicative of a Tc1-type cytokine response. Thus, PTD-NY-ESO-1 accesses the cytoplasm by protein transduction, is processed by the proteasome, and NY-ESO-1 peptides presented by HLA class I elicit NY-ESO-1-specific T lymphocytes. (Cancer Res 2005; 65(21): 10041-9)

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Section: Introductionsupporting

confidence: 69%

Protein Transduction of Dendritic Cells for NY-ESO-1-Based Immunotherapy of Myeloma

et al. 2005

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“…In particular, the overexpression of KLF4 is intriguing as it has been reported to mediate the transcriptional repression of the CCND1 promoter (Shie et al, 2000); the low or background levels of CCND1 found in the patients with the t(4;14) (data not shown) may therefore be related to its increased expression. This finding may suggest that cases with the t(4;14) are characterized by the activation of proapoptotic pathways, and thus may be more likely to respond to chemotherapy regimens, consistently with recently reported data (Stewart et al, 2004). During the revision process of this manuscript, a study was published describing the gene expression profiling of t(4;14) MM cases (Dring et al, 2004) whose results only partially overlap with our own, probably because of the different analysis criteria.…”

Section: But Not Pcl Cases) Have Suggested That Normalsupporting

confidence: 41%

Gene expression profiling of plasma cell dyscrasias reveals molecular patterns associated with distinct IGH translocations in multiple myeloma

et al. 2005

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Multiple myeloma (MM) is the most common form of plasma cell dyscrasia, characterized by a marked heterogeneity of genetic lesions and clinical course. It may develop from a premalignant condition (monoclonal gammopathy of undetermined significance, MGUS) or progress from intramedullary to extramedullary forms (plasma cell leukemia, PCL). To provide insights into the molecular characterization of plasma cell dyscrasias and to investigate the contribution of specific genetic lesions to the biological and clinical heterogeneity of MM, we analysed the gene expression profiles of plasma cells isolated from seven MGUS, 39 MM and six PCL patients by means of DNA microarrays. MMs resulted highly heterogeneous at transcriptional level, whereas the differential expression of genes mainly involved in DNA metabolism and proliferation distinguished MGUS from PCLs and the majority of MM cases. The clustering of MM patients was mainly driven by the presence of the most recurrent translocations involving the immunoglobulin heavy-chain locus. Distinct gene expression patterns have been found to be associated with different lesions: the overexpression of CCND2 and genes involved in cell adhesion pathways was observed in cases with deregulated MAF and MAFB, whereas genes upregulated in cases with the t(4;14) showed apoptosis-related functions. The peculiar finding in patients with the t(11;14) was the downregulation of the a-subunit of the IL-6 receptor. In addition, we identified a set of cancer germline antigens specifically expressed in a subgroup of MM patients characterized by an aggressive clinical evolution, a finding that could have implications for patient classification and immunotherapy.

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“…The dysregulation of TACC3 and MMSET in t(4;14) POS patients has been investigated in several studies. 14,37,38 TACC3 was assayed by qRT-PCR by Stewart et al 37 and a 2-fold increase was reported in t(4;14) POS patients. In our qRT-PCR cohort, we detected an approximate 2-fold difference (REL, 1.17 versus 3.90), however, this difference in mean values was largely due to one outlier and was not statistically significant.…”

Section: Discussionmentioning

confidence: 99%

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

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et al. 2005

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Correlation of TACC3, FGFR3, MMSET and p21 expression with the t(4;14)(p16·3;q32) in multiple myeloma

Abstract: samples showed a joint up-regulation of TACC3, MMSET and p21. Although a poor prognosis is linked with elevated MMSET expression, an extended follow-up period will be required to evaluate the significance of elevated TACC3 and p21 expression in this subgroup of MM.

Cited by 39 publications

References 14 publications

Protein Transduction of Dendritic Cells for NY-ESO-1-Based Immunotherapy of Myeloma

Protein Transduction of Dendritic Cells for NY-ESO-1-Based Immunotherapy of Myeloma

Gene expression profiling of plasma cell dyscrasias reveals molecular patterns associated with distinct IGH translocations in multiple myeloma

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

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