ISPO

The tyrosine kinase inhibitor sti571 downregulates gene expression by reducing histone h4 acetylation and histone deacetylase (hdac) expression.

G Brusa, PhD, MA Santucci, F Campanini, L Pattacini, M Mancini, L Mazzacurati, M Baccarani

University of Bologna Medical School, Bologna, Bologna Italy

STI571 is a powerful inhibitor of abl tyrosine kinase, whose activity results from its competition with ATP for the ATP-binding site of c-abl protein catylitic subunit. Preclinical studies have shown that STI571 antiproliferative activity is directed against p210 bcr-abl-expressing cell lines and clonal hematopoietic progenitors of Chronic Myeloid Leukemia (CML). However, the mechanisms undelying its function have not been elucidated yet. We investigated on the interactions of STI571 with the basic biomolecular machinery involved in regulated gene expression. To the purpose, we used as experimental model 32D cell clones transducing a temperature sensitive p210 bcr-abl construct, whose product owns tyrosine kinase activity at 33deg, but not at 39deg. By a competitive PCR, we compared in p210 bcr-abl-transduced cell clones and in parental cell line the effects of exposure to 1 microM STI571 on the expression levels of genes critical for cell cycle progression (p21WAF1/CIP1), apoptotic cell death (bax), DNA repair (gadd45) in addition to these of bcr-abl fusion gene. In addition, we assayed the H4 histone acetylation and the histone deacetylase (HDAC) expression. Results of our study are consistent with STI571 ability of downregulating the transcription of all above genes and decreasing the acetylated state of H4 histone as well as HDAC levels. We can conclude that STI571 acts on p210 bcr-abl-induced constitutive transduction of the mitogenic signal by revoking the illegitimate stimulus that it brings forth intermediate transcription factors, such as c-myc. Decreased histone acetylation may prelude to the restoration of regulated transcriptional activity and recovery of HDAC enzyme function.

KEY WORDS: Chronic Myeloid Leukemia, bcr-abl, cell cycle, p21/WAF1/CIP1, gadd45, bax.

For more information, contact ssantucc@med.unibo.it

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Novel Therapies, Part 1.

This presentation was a winner in our poster contest and was recognized with the Symposium Presidents' Award for Scientific Excellence.

http://www.cancerprev.org/Journal/Issues/26/101/1195/4617