Mantle Cell Lymphoma
Dr. Armin Pscherer
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).
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.
The question arises: Which chromosomal aberrations are to which extent responsible for the functional degenerations of the certain cancer cell?
Our group is anxious to extend 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 division to a more functional prospect. Both malignancies exhibit different aggressiveness but also strong overlapping characteristics of phenotypical and genetical manner (Korz et al. ‘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’ Blood 99, 4554-4561, 2002). 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 indices
Both NHL-entities also display asimilar pattern of genomic aberrations and genetic defects. These inactivated and rearranged genes and loci are studied and analyzed.
By using 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).
• „Knocking-down“ overexpressed genes by the RNAi-technology (potential oncogenes.
Both strategies use the recombinase-mediated cassette exchange (RCME) to this end (see Methods: Cellular transgenesis systems, see also Pscherer et al. ‘ Antagonizing inactivated tumor suppressor genes and activated oncogenes by a versatile transgenesis system: Application in mantle cell lymphoma', FASEB Journal 20, 1188-1190, 2006).
These gene modulations can be functionally analyzed in cells which retained unchainged other disease-specific chromosomal aberrations. The effects of the different gene alterations in the cells are 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.