Joop Gaken

Tumour specific induction of apoptosis
Autologous bone marrow transplantation is an alternative therapeutic option for patients suffering from haematological malignancies lacking an HLA compatible donor. However, disease relapse remains a primary cause of death due in part to autograft contamination with clonogenic tumour cells. The multiple purging strategies developed to date have proven ineffective in eradicating the tumour cells from the autologous haemopoeitic stem cell grafts. Pharmacological and immunological approaches to eliminate the leukaemic cells from autografts are often toxic to the normal haematopoietic progenitors, limiting the clinical utility. Reduction of the tumour burden by positive/ negative selection procedures require the presence of differentially expressed membrane antigens on either the tumour cells or the normal haematopoietic progenitors and stem cells which is not generally the case in haematological malignancies. In order to improve the efficacy of cell purging we are studying a chicken anemia virus (CAV) derived protein called Apoptin. Apoptin is a protein which has been shown to induce apoptosis in a variety of human malignant and transformed cells, but not in normal cells

MicroRNA target discover
MicroRNAs(miRNAs) are a novel class of small RNA molecules that can regulate the expression of many genes.They have been shown to be involved in many fundamental processes such as differentiation, proliferation, apoptosis and play a role in cancer. Several microRNAs can act as either oncogenes or tumour suppressor genes. It is currently thought that in humans miRNAs acts mainly by mediating specific translational inhibition and to a lesser extent degradation of mRNA targets.

The role and targets of most miRNAs in humans are largely unknown. Computational identification of miRNAs targets using various algorithms provide some insight into the miRNAs targets,however the drawbacks of these predictions are that they all have a substantial false positive rate and may be biased as they are mostly based on the few known miRNA:target gene interactions.The need for a functional assay to identify the miRNA target is the need of the hour.

We have developed a novel functional assay to enable identification of functional miRNA targets. In a pilot project we used mir130a and its verified target v-maf musculoaponeurotic fibrosarcoma oncogene homolog B(MAFB)as a proof of concept,this identified a further panel of mir130a targets none of which were identified as potential targets of mir130a by the available target pridiction programmes.