Abstracts (poster) - Wissenschaft Online

Cordula Tschuch, Angela Schulz, Armin Pscherer, Meinhard Hahn, Peter Lichter, Daniel
Mertens
Functional analysis of candidate genes localized in 13q14.3, a
region commonly affected in B-CLL
In B-cell Chronic Lymphocytic Leukemia (B-CLL), loss of region 13q14.3 is the most
frequent genomic imbalance. Several characteristics of this region point to an epigenetic
pathomechanism: 1) candidate genes lack point mutations, 2) these genes are
downregulated in tumors, 3) the presence of large non-coding RNA genes is reminiscent
of imprinted regions where only one gene copy is active. Recently, we could show that
the two copies of the critical region are replicating asynchronously suggesting differential
chromatin packaging. Furthermore, a number of genes in the region are monoallelically
expressed in healthy probands. This led us to the functional characterization of genes in
the critical region which will allow identification of their role in the molecular
pathomechanism.
Candidate genes were overexpressed in a hematopoetic cell line and RNAi technology
was used for the knock down of candidate genes. After modulation of expression, RNA
was isolated at different time points to identify effects in downstream target genes via
expression profiling.
After overexpression and knock down of candidate genes, we could identify target genes
involved in pathways for which a tumor suppressor function has been described. Thus,
NOTCH signaling is involved in regulation of cell cycle, apoptosis and survival.
Furthermore, we showed that candidate genes are involved in NF•B signaling. This
pathway has the potential to promote survival of B-cells and plays a major role in B-cell
development.
Our analysis shed light on the function and the pathways involved in the
pathomechanism localized in 13q14.3. The essential role in early B-cell development,
make them highly interesting candidate pathways for elucidation of the pathomechanism
in B-CLL.
contact:
Dr. Cordula Tschuch
German Cancer Research Center
c.tschuch@dkfz.de
Im Neuenheimer Feld 580
69120 Heidelberg (Germany)