Chromosomal translocations of the human MLL gene located on the long arm of chromosome 11 (q23) are associated with high-risc acute leukemias. In all translocations of the MLL gene, this particular gene is reciprocally recombined with "translocation partner genes", resulting in the generation of two new fusion genes ("chimerization"). Until now, more than 50 different translocation partner genes have been identified in leukemia patients. Due to the illegitimate recombination process, two "fusion genes" can be identified at the fusion sites of the resulting "derivative chromosomes". These fusion genes carry fused open reading frames and are actively transcribed in the leukemic cell population. Therefore the hypothesis was posed that the fusion genes encode oncogenic proteins that trigger the leukemogenic process. For several translocation, e.g. the t(9;11) translocation and two different t(11;19) translocations this has been proven in experiments using retroviral gene transfer into murine hematopoietic stem cells. After replating-experiments in soft agar, single colonies were transferred into isogenic mice and acute myeloid leukemia developed after several months.
Our laboratory is mainly focussed on the chromosomal translocation t(4;11). This particular translocation is predominantly diagnosed in acute lymphoblastic leukemia of infants (patients below one year of age) and early childhood. We are interested in the function of the wildtype proteins MLL and AF4, as well as the potential oncogenic function of the chimeric proteins MLL/AF4 and AF4/MLL. To our knowledge, no animal model is available. Therefor, we are aiming to understand the function(s) of the MLL fusion proteins by using an in vitro t(4;11) test system, and subsequently, to develop an animal model system for this specific leukemia.
Another focus in our laboratory is the illegitimate recombination process that is leading to illegitimate recombinations of the human MLL gene. We are interested in the endogenous molecular mechanisms that trigger such illegitimate recombination events.
A third focus is the diagnosis of MLL translocations. Different diagnostic tools have been developed over the past years that enables us to diagnose any chromosomal rearrangement of the MLL gene at the chromosomal level. This novel techniques has led to the discovery of 16 novel MLL fusion partners over the last 3 years. In particular, chromosomal fusion sites of individual leukemia patients were cloned and sequences. The latter technique enables us to identify patient-specific DNA sequences that can be used to monitor individual t(4;11) patients for minimal residual disease (MRD), and thus, for the efficacy of current treatment protocols.