A variety of human malignancies show loss of a critical region in chromosomal band 13q14.3 that harbors a tumor suppressor mechanism. In more than 50% of patients suffering from B-cell chronic lymphocytic leukemia (B-CLL), the most common leukemia of the western world, this region is deleted. Despite extensive efforts from a number of labs, the molecular nature of this mechanism has proven elusive. The region contains long non-coding RNA genes, micro-RNA genes and multicistronic transcripts. We have recently been able to show a complex epigenetic regulatory mechanism in this region which involves DNA-methylation, asynchronous replication timing and monoallelic expression. This epigenetic mechanism can explain some of the genetic peculiarities observed in patients. What we are currently doing is to elucidate the intricacies of the regulatory mechanism characterize the molecular function of the candidate tumor suppressor genes in the critical region. With the insights gained, we hope to impact not only on the diagnosis of B-CLL patients but also open new avenues for treatment strategies.

How does the microenvironment support leukemic cells?
Malignant cells of patients suffering from B-cell chronic lymphocytic leukemia (B-CLL) accumulate in the lymphatic organs and peripheral blood and finally result in the failure of the immune system. However, if the malignant cells are cultured in vitro, they rapidly undergo apoptosis unless they are supported by non-malignant stroma cells. This suggests an intimate interaction of the leukemia cells with their microenvironmant and an essential dependance on survival signals from the supporting cells. In a systematic approach, we want to characterize the delicate interplay of these anti-apoptotic signals which have been discovered to date. Even though each of these signals prolongs the life of CLL cells in vitro, none of them can alone substitute the anti-apoptotic effect that the stromal cells have on the leukemic cells in vitro. If we are able to describe this crucial balance of supporting signals and identify its central nodes, these could be directly targeted in the patients using low but effective doses of compounds, some of which are already clinically established.