The (12;21)(p13;q22) Tel/Aml1 (Etv6/Runx1) chromosomal translocation is the most frequent translocation in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with about 25% of children suffering from BCP-ALL harboring this translocation. BCP-ALL is a heterogenous disease with a variety of genetic abnormalities e.g. the deletion of the still functional Tel allele. The Tel-Aml1 translocation results in an arrest of differentiation at the level of pro B-cells and the proliferation of this cell type. It was shown in humans that Tel/Aml1 is detectable as early as in CD19+ but not in the more immature CD34+CD19- cells. Interestingly, the incidence for the Tel/Aml1 translocation is far higher than the actual incidence of actual disease development leading to the hypothesis that additional hits must occur for BCP-ALL to develop. So far, no suitable mouse model exists to investigate the role of Tel/Aml1 and additional hits in the context of BCP-ALL. We therefore developed a mouse model where Tel/Aml1 is expressed specifically in CD19+ B-cells. In this study we could demonstrate that expression of Tel/Aml1 has no influence on hematopoiesis and does not result in leukemia. However, expression of genes relevant for B-cell development were shown to be altered in Tel/Aml1 tg mice, suggesting a crucial role for Tel/Aml1 in B-cells.
Heterozygous deletion of the tumor suppressor Ink4a/Arf in Tel/Aml1 tg mice did not lead to leukemia, however, resulted in reduced numbers of pre and immature B-cells and elevated numbers in mature B-cells.
Transduction of Ink4/Arf-/- cells with Tel/Aml1 resulted in various diseases in recipient mice but not in Tel/Aml1+ B-cell leukemia.
Expression of a second hit (Fli1) did not result in B-cell leukemia but due to the strong oncogenic effect of Fli1 mostly in erythroleukemia.