We have identified a novel mammalian A-type cyclin, cyclin A1, which we have shown to be expressed at highest levels if not exclusively in the testis in mice and humans. Targeted mutagensis in mice revealed that during normal development, cyclin A1 functions uniquely in the progression of male germ cells into the first meiotic division. Human cyclin A1 is also highly expressed in leukemic cells from patients with acute myeloid leukemia. To test the hypothesis that the aberrant high levels of cyclin A1 were causal in the leukemic phenotype, i.e., acting as an oncogene, we generated transgenic mice in which cyclin A1 was expressed under the direction of the human cathepsin G (hCG) promoter in myeloid precursor cells. The transgenic animals exhibited abnormal myelopoiesis and developed acute myeloid leukemia. We have also recently observed high levels of cyclin Al expression in testicular tumors of the highly invasive embryonal carcinoma class but not in the more common and less invasive seminoma. We propose that cyclin A1 represents a novel target for drug intervention because of: (i) its causal role in myeloid leukemia, which we have demonstrated; (ii) its elevated expression in a restricted subset of invasive testicular tumors; and (iii) importantly, its remarkable tissue specificity of function (testis) during normal development. That is, if interference with cyclin A1 function in leukemic cells can revert their tumorigenic phenotype, the lack of its function would be predicted to not affect any other systemic organ other than the testis in men and to have no systemic effects in women.
The aims of this present application are therefore: (1) To ask if inhibiting the expression of cyclin A1 in leukemic cells in vitro and in vivo, initially using antisense approaches, can revert the leukemic phenotype; and (2) to develop efficient in vitro kinase assays for screening pharmacological targets for inhibition specifically for cyclin A1/Cdk function. These experiments will initially involve identifying the preferred in viva Cdk partner for cyclin A1 in leukemic cells and then characterization of the cyclin A1/Cdk complex on selected substrates to optimize an in vitra kinase assay suitable for large-scale screening for inhibitors of the kinase assay.
| Ekberg, Jenny; Landberg, Goran; Holm, Caroline et al. (2004) Regulation of the cyclin A1 protein is associated with its differential subcellular localization in hematopoietic and leukemic cells. Oncogene 23:9082-9 |
