ARGININE BUTYRATE DOWN-REGULATES P(210) BCR-ABL EXPRESSION AND INDUCES APOPTOSIS IN CHRONIC MYELOGENOUS LEUKEMIA-CELLS

Downregulation of bcr-abl expression in the chronic myelogenous leukem ia cell line K562 using antisense oligonucleotides has been shown to e nhance the sensitivity of the cells to apoptotic stimuli, suggesting t hat p(210) bcr-abl, like bcl-2 functions as an anti-apoptosis factor ( McGahon A et al, Blood 1994, 83: 1179). In these experiments, the inhi bition of p(210) bcr-abl expression alone was not sufficient to induce apoptosis. We demonstrated that exposure to low doses (0.5 mM) of a b utyric acid analog, arginine butyrate, was capable of inducing apoptos is in selected leukemia cell lines, including K562 cells, and in fresh leukemia cells from patients with chronic myelogenous leukemia. To fu rther explore the mechanisms of this effect, we examined expression of p(210) bcr-abl after butyrate exposure and found a dose-related inhib ition of p(210) bcr-abl protein without concordant change in other pho sphoproteins, including the JAK-1 kinase. Further analysis revealed th at the inhibition of bcr-abl expression occurs due to transcriptional regulation of the bcr-abl gene by arginine butyrate. These results sug gest that arginine butyrate and other butyrate analogs alone or in com bination may he useful in the therapy of patients with chronic myeloge nous leukemia or bcr-abl expressing acute leukemias.