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Human myeloma cell lines gene expression profiling

ABSTRACT: In order to investigate the patterns of genetic lesions in a panel of 23 Human Multiple Myeloma Cell Lines (HMCLs), we made a genomic integrative analysis involving FISH and both gene expression and genome-wide profiling approaches. The expression profiles of the genes targeted by the main IGH translocations showed that the WHSC1/MMSET gene involved in t(4;14)(p16;q32) was expressed at different levels in all of the HMCLs, and that the expression of the MAF gene was not restricted to the HMCLs carrying t(14;16)(q32;q23). Supervised analyses identified a limited number of genes specifically associated with t(4;14) and involved in different biological processes. The signature related to MAF/MAFB expression included the known MAF target genes CCND2 and ITGB7, as well as genes controlling cell shape and cell adhesion. Genome–wide DNA profiling allowed the identification of a gain on chromosome arm 1q in 88% of the analyzed cell lines, together with recurrent gains on 8q, 18q, 7q and 20q; the most frequent deletions affected 1p, 13q, 17p and 14q; and almost all of the cell lines presented LOH on chromosome 13. Two hundred and twenty-two genes were found to be simultaneously overexpressed and amplified in our panel, including the BCL2 locus at 18q21.33. Our data further support the evidence of the genomic complexity of multiple myeloma and reinforce the role of an integrated genomic approach in improving our understanding of the molecular pathogenesis of the disease. Keywords: cell line comparison

ORGANISM(S): Homo sapiens

PROVIDER: GSE6205 | GEO | 2006/12/28

SECONDARY ACCESSION(S): PRJNA100619

REPOSITORIES: GEO

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Transcription profiling of human myeloma cell lines (23)

Project description:In order to investigate the patterns of genetic lesions in a panel of 23 Human Multiple Myeloma Cell Lines (HMCLs), we made a genomic integrative analysis involving FISH and both gene expression and genome-wide profiling approaches. The expression profiles of the genes targeted by the main IGH translocations showed that the WHSC1/MMSET gene involved in t(4;14)(p16;q32) was expressed at different levels in all of the HMCLs, and that the expression of the MAF gene was not restricted to the HMCLs carrying t(14;16)(q32;q23). Supervised analyses identified a limited number of genes specifically associated with t(4;14) and involved in different biological processes. The signature related to MAF/MAFB expression included the known MAF target genes CCND2 and ITGB7, as well as genes controlling cell shape and cell adhesion. Genomeâwide DNA profiling allowed the identification of a gain on chromosome arm 1q in 88% of the analyzed cell lines, together with recurrent gains on 8q, 18q, 7q and 20q; the most frequent deletions affected 1p, 13q, 17p and 14q; and almost all of the cell lines presented LOH on chromosome 13. Two hundred and twenty-two genes were found to be simultaneously overexpressed and amplified in our panel, including the BCL2 locus at 18q21.33. Our data further support the evidence of the genomic complexity of multiple myeloma and reinforce the role of an integrated genomic approach in improving our understanding of the molecular pathogenesis of the disease. Experiment Overall Design: 23 Human Multiple Myeloma Cell Lines (HMCLs)

2008-06-14 | E-GEOD-6205 | biostudies-arrayexpress

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Project description:Multiple myeloma (MM) is characterized by recurrent chromosomal translocations. The translocation t(4;14)(p16;q32) is one of the most common translocation in MMs, affecting 15% of patients, and is associated with very poor prognosis. The histone methyltransferase (HMTase) MMSET is universally overexpressed in t(4;14) MM as a result of the t(4;14) translocation. MMSET is capable of producing 3 major isoforms, the full length MMSET II, short isoforms REIIBP and MMSET I. MMSET II has been suggested to play an important tumorigenic role in t(4;14) MM, but little is yet known about whether and how the MMSET short isoforms contribute to MM tumorigenesis. The aim of this study is to characterize MMSET I roles and determine its downstream targets in t(4;14) MM. In t(4;14) MM cells MMSET I knockdown with shRNAs induced cell apoptosis, reduced colony formation and inhibited tumorigenicity in vivo. We also found MMSET I knockdown decreased GLO1 expression, and ectopic MMSET I increased GLO1 expression, suggesting that MMSET I is an upstream regulator of GLO1. Further analysis indicated that MMSET I bound to GLO1 promoter region and depended on its C-terminus to regulate GLO1 expression. Our preliminary data suggested that MMSET I is an oncoprotein and could regulate GLO1 expression in t(4;14) multiple myeloma cells.

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Gene expression profiling of KMS11 parental (PAR), TKO and 8 reconstituted lines

Project description:NSD2, a histone lysine methyltransferase, is overexpressed as a result of the t(4;14) translocation that is associated with 15-20% of multiple myeloma. Earlier studies have indicated that NSD2 may be involved in myelomagenesis and suggested that it may be a target for myeloma therapy. Here we show that NSD2 is required for clonogenic growth, adherence and proliferation on bone marrow stroma, and tumorigenesis of t(4;14)+ but not t(4;14)- myeloma cells, in a methyltransferase activity dependent manner. Furthermore, we found that PHD domains are important for NSD2 cellular activity and biological functions by recruiting it to oncogenic gene loci and driving downstream transcription activation events. These results strengthened the disease link of NSD2 and provided a basis that targeting NSD2 may be a therapeutic strategy in multiple myeloma patients with t(4;14) translocation. Our data also revealed multiple domains in the protein for possible chemical modulation. To elucidate the mechanisms underlying the oncogenic potential of NSD2 in myeloma, we performed microarray analysis on KMS11 parental (PAR), TKO and 8 reconstituted lines. Based on the whole-genome expression profile, the 10 samples clearly fell into 4 clusters – (1) PAR; (2) TKO; (3) WT, WT+MMSET I, 526-1240 and 526-1365; and (4) CDM, CDM+MMSET I, MMSET I and H762Y Biological triplicates of cell cultures of indicated lines were harvested in TRIzol (Invitrogen) and characterized by human U133 plus 2.0 Affymetrix GeneChip. The gene expression data was normalized using the Robust Multiarray Averaging (RMA) method and log2 transformed before comparisons.

2013-08-22 | E-GEOD-50072 | biostudies-arrayexpress

NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming [TKO]

Project description:NSD2 (also named MMSET and WHSC1) is a histone lysine methyltransferase that is implicated in diverse diseases and commonly overexpressed in multiple myeloma due to a recurrent t(4;14) chromosomal translocation. However, the precise catalytic activity of NSD2 is obscure, preventing progress in understanding how this enzyme influences chromatin biology and myeloma pathogenesis. Here we show that dimethylation of histone H3 at lysine 36 (H3K36me2) is the principal chromatin-regulatory activity of NSD2. Catalysis of H3K36me2 by NSD2 is sufficient for gene activation. In t(4;14)-positive myeloma cells, the normal genome-wide and gene-specific distribution of H3K36me2 is obliterated, creating a chromatin landscape that selects for a transcription profile favorable for myelomagenesis. Catalytically active NSD2 confers xenograft tumor formation and invasion capacity upon t(4;14)-negative cells and NSD2 promotes oncogenic transformation of primary cells in an H3K36me2-dependent manner. Together our findings establish H3K36me2 as the primary product generated by NSD2, and demonstrate that genomic disorganization of this canonical chromatin mark initiates oncogenic programming. Genome-wide expression profiling of KMS11 and t(4;14) translocation knockout (TKO) cells. Each cell line is tested in triplicate.

2011-11-29 | E-GEOD-29148 | biostudies-arrayexpress

A novel non-coding RNA within WHSC1 is over-expressed in t(4;14)-positive multiple myeloma and other cancers

Project description:We designed oligonucleotide tiling arrays spanning the t(4;14) breakpoint region on chromosome 4 to identify additional oncogenic RNAs in an unbiased fashion. Four (4) multiple myeloma bone marrow samples with t(4;14) and twelve (12) MM BM samples without t(4;14) were analyzed. Furthermore, seven (7) bladder (1 normal, 6 malignant), eight (8) colon (1 normal, 7 malignant) and eight (8) esophagus (2 normal, 6 maligant) tissue samples were analyzed. Finally, five (5) multiple myeloma cell line samples with t(4;14) - three (3) of LP-1 and two (2) of H929 - and three (3) MM cell line samples and three (3) non-MM cell line samples without t(4;14) - three (3) of U266 and three (3) of Hela - were analyzed.

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