Functional Tumorgenetics
Fig. 1: Karyotyp-Analysis of a typical MCL cell clone showing loss (e.g. chr.13) as well as gain (e.g. chr.7) and structural rearrangement (e.g. chr der18) of chromosomal material.
© dkfz.de
Like all cancer cells leukemias and lymphomas are also based on degenerated cells, which show a significant difference to normal cells regarding their genetic material. The genetic material of a normal mammal cell consists of 2 sets of 22 chromosomes, plus 1 X-chromosome and 1 Y-chromosome (male), or plus 2 X-chromosomes (female). In a cancer cell this constellation is dearranged by loss, gain and structural rearrangements of chromosomes, the cancer cell exhibits so called chromosomal aberrations (Fig. 1).
The question arises: Which chromosomal aberrations are to which extend responsible for the functional degenerations of the certain cancer cell ?
Our group is anxious for extending the descriptive studies about chromsomal aberrations of the the leukemic human neoplasias B-CLL (chronic lymphocytic leukemia of the B-cell type) and MCL (mantle cell lymphoma) accomplished so far in our department to a more functional prospect. Both malignancies exhibit different aggressiveness but also strong overlapping characteristics of phenotypical and genetical manner. These Non-Hodgkin-lymphomas (NHLs) are phenotypically defined by the same functional degenerations:
- arrested and incomplete grade of differentiation
- defective induction of apoptosis
- for tumor cells quite unusual low proliferation indeces
Both NHL-entities also display an almost identical pattern of genomic aberrations and genetic defects. These inactivated and rearranged genes and loci are studied and analyzed to a such an extend, that these data are suited for a detailed analyzes of the functional relevance regarding the postulated tumorsuppressor genes, oncogenes (ATM, BCMS, Bcl-2, c-myc, cyclin D1, p53, p16) and the up to now not further focused but also significantly involved genomic loci in B-CLL and MCL.
We use two strategies for modifying gene-expression of disease relevant genes and analyzing their function:
- Complementation of deleted or mutated genes by stable transfection of their genomic sequences (potential tumorsuppressor genes) (Fig.3 see other project)
- „Knocking-down“ overexpressed genes by the RNAi-technology (potential oncogenes) (Fig.5 see other project)
These gene modulations can be functionally analyzed in cells which retained other disease-specific chromosomal aberrations unchanged. The effects of the different gene alterations in the cells would be analyzed with:
- gene expression studies (cDNA-chip technology and quantitaive real-time PCR) and
- phenotypical cell assays, proliferation-, apoptosis- and differentiation-assays, testing for the typical functional degenerations of B-CLL and MCL cells.
projects:
Publications concerning this work
- Antagonizing inactivated tumor suppressor genes and activated oncogenes by a versatile transgenesis system: application in mantle cell lymphoma.
- Evidence for distinct pathomechanisms in B-cell chronic lymphocytic leukemia and mantle cell lymphoma by quantitative expression analysis of cell cycle and apoptosis-associated genes.
- Ala228 variant of trail receptor 1 affecting the ligand binding site is associated with chronic lymphocytic leukemia, mantle cell lymphoma, prostate cancer, head and neck squamous cell carcinoma and bladder cancer.
- Genomic DNA-chip hybridization in t(11;14)-positive mantle cell lymphomas shows a high frequency of aberrations and allows a refined characterization of consensus regions.