TY  - GEN
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/9641/
A1  - Farfsing, Alexandra
N2  - The two B cell non-Hodgkin lymphoma entities chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are lymphoproliferative neoplasms characterized by different aggressive clinical courses. However, they show striking geneotypic similarities like recurrent chromosomal gains of 3q25 q29, 12q13 q14 and 18q21-q22. The genetic pathomechanisms affected by these aberrations are mainly not understood. Several studies reported the high resolution detection of chromosomal imbalances in MCL and CLL using array CGH, accurately defining the gained regions. These imbalances, however, still contain too many genes in order to enable a reasonable selection of candidates. The aim of the present study was to identify genes with oncogenic potential in recurrently gained chromosomal regions of MCL and CLL using high resolution expression arrays, followed by studying the effect of gene silencing on cell proliferation. First, the expression of 24 primary CLL and 6 primary MCL patients, as well as 6 cell lines was profiled, and the identified genes in the three gained regions (3q, 12q, and 18q) were compared to published data. Second, the 72 candidate genes derived from this analysis were functionaly investigated by the use of an RNA interference screen in a multiwell format. Third, the changes in cell viability were validated in primary CLL cells and downstream effects of the identified candidate genes were analyzed. The three genes CCDC50, SERPINI2 and SMARCC2 emerged as candidates mediating a reduction in cell viability in cell lines and in primary CLL cells. CCDC50 was identified as a candidate gene with a 3.5-fold mean overexpression in primary cells of MCL and CLL patients. Gene knockdown and reporter gene assays revealed a role of CCDC50 in promoting cell survival. MCL and CLL cell lines with stable CCDC50 knockdown revealed 75% less proliferation than the parental cells. Interestingly, and in contrast to results shown in Hela cells, the data of this study gave rise to a survival stimulating effect of CCDC50. TNF alpha induced NFkB activation revealed a direct correlation of inducibility and CCDC50 expression. Genome wide expression profiling studies identified several target genes of p53 signaling pathways as upregulated in accordance with low CCDC50 transcript levels. Overexpression of pro-apoptotic genes like TP53I3 and BAX and downregulation of apoptosis-protecting genes like BNIP3L and GADD45A were a plausible cause for the reduction in cell viability in primary CLL cells and cell lines after CCDC50 silencing. In conclusion, CCDC50 was identified as activated candidate gene in MCL and CLL that is responsible for cell survival and plays a role in NFkB and p53 signaling pathways.
TI  - Identification and functional characterization of candidate genes in recurrently gained genomic regions of mantle cell lymphoma and chronic lymphocytic leukemia
Y1  - 2009///
N1  - Teile in: Leukemia
AV  - public
ID  - heidok9641
KW  - Mantelzell Lymphom 
KW  -  chronisch lymphatische Leukämie 
KW  -  RNA Interferenz 
KW  -  Expressionsprofile
KW  -  OnkogeneMantle cell lymphoma 
KW  -  chronic lymphocytic leukemia 
KW  -  RNA interference 
KW  -  expression profiling 
KW  -  oncogene
ER  -