Molecular mechanisms of the TEL-AML1 fusion gene in leukemia

Introduction: The t(12;21) chromosomal translocation and its molecular equivalent the TELAML1 fusion gene is with a frequency of 25% the most common genetic abnormality in childhood B-precursor acute lymphoblastic leukemia. The reported relapse rate varies between different treatment protocols and is, in the BMF studies, about 20%. Thus, it is the largest molecularly characterized group of relapses in children with ALL. The TEL-AMLI gene fusion can be induced by apoptosis, thereby rescuing the affected cell from programmed cell death. The fusion gene can be found at birth in the majority of children with TEL-AMLI positive ALL indicating that this gene fusion is an early event in leukemogenesis which occurs already in utero. Since the frequency of TEL-AMLI positive cord blood samples from healthy newboms is 100 times the incidence of t(12;21) positive ALL additional molecular changes are assumed to be necessary for the clinical manifestation of leukemia. Despite increasing knowledge an the function of the two genes TEL and AML1, the function of the fusion gene as well as its contribution to the malignant transformation is largely unknown. Aims: The aim of this study is to investigate the functional contribution of the TEL-AML1 fusion product to the leukemic cell phenotype as well as its impact an cell survival/apoptosis, cell cycle regulation and tumor suppressor genes. Experimental procedures: We will employ the RNA interference technology, a new and highly specific approach, to block the expression of the TEL-AMLI gene fusion in the t(12;21) positive BCP ALL cell line REH. For this purpose sequence specific small interfering RNA will be delivered to REH cells by cationic liposome-mediated transfection. Using this model system we will analyze whether cells undergo apoptosis after blockage of the fusion transeript. The influence of the gene fusion an molecular mechanisms of apoptosis, an cell cycle regulation as well as an tumor suppressor genes will be investigated. By this approach we will find out whether the TEL-AML1 gene fusion can be molecularly targeted and may thus provide the basis for a new form of therapy. Further, TEL-AML1 dependent genes will be identified and their function charaeterized. This will contribute to a better understanding of the biology of this subgroup of childhood ALL.