QUANTITATIVE AND QUALITATIVE VARIATION OF ETS-1 TRANSCRIPTS IN HEMATOLOGIC MALIGNANCIES

The ETS family proteins have a conserved DNA-binding domain and act as transcription factors. Three domains have been recently defined in hu man ETS-1 proteins and their role could depend upon the nature of alte rnative transcripts according to whether they possess or lack DNA bind ing and/or transcriptional activation domain and also point mutation t hat could affect these important domains. Expression of ETS-1 gene is very complex and is controlled at several levels: the initiation of tr anscription, alternative splicing, post-translational modification, an d protein stability. As a selection apparently exists for ETS-1 gene a ctivation in hematopoietic cells, we investigated a relation between q uantitative and qualitative ETS-1 expression and leukemogenesis. Using Northern blot, polymerase chain reaction (PCR), and single strand con formation polymorphism (SSCP) methods, we analyzed quantitative and qu alitative ETS-1 expression in a variety of hematological pathologies a nd cell lines of different origin. Two ETS-1 transcripts of 6.8 and 2. 7 kb, resulting from differential polyadenylation site utilization and exhibiting different stability, were observed. We identified, in a gr eat number of patients, the four alternative ETS-1 products, but the r elative extent significance of the four transcripts was very different from one patient to another. A non-conservative mutation observed in one case of T-cell acute lymphoblastic leukemia (T-ALL) and in the ETS -1 transactivation domain raised the question of suppressor activity f or some ETS-1 products, as it is now known that activators and repress ors can be encoded by the same gene and consistently co-expressed in v ivo.