REGULATION OF THE C-JUN GENE IN P210 BCR-ABL TRANSFORMED-CELLS CORRESPONDS WITH ACTIVITY OF JNK, THE C-JUN N-TERMINAL KINASE

Activity of the c-jun N-terminal kinase (JNK) has been shown in hemato poietic cells transformed by p210 BCR-ABL. However, analysis has not b een reported for hematopoietic cells on the consequences of this activ ity for c-jun promoter regulation within its distinctive proximal 8-ba se consensus CRE-like element, an element linked to JNK-mediated incre ase in c-jun transcription. In the present study, regulation of the pr oximal c-jun promoter was studied in murine myeloid cells transformed by p210 BCR-ABL. Promoter regulation in p210 BCR-ABL transformed cells was compared with regulation of the promoter in nontransformed interl eukin-3 (IL-l)-dependent parental cells. The composition of nuclear AP -1 proteins contained within cells with p210 BCR-ABL, and their bindin g to the c-jun promoter proximal CRE-like element, was compared with t he composition and binding of AP-1 proteins in IL-3-treated parental c ells without p210 BCR-ABL. The present analysis found fivefold increas ed c-jun transcription occurring in p210 BCR-ABL transformed murine my eloid cells possessing a corresponding magnitude of increased kinase a ctivity of JNK, compared with IL-3-stimulated parental cells, Augmente d JNK activity was accompanied by increased nuclear abundance of c-jun and c-fos proteins that bound specifically to the proximal c-jun prom oter CRE element. Also, representative human leukemic cell lines expre ssing p210 BCR-ABL and possessing abundant kinase activity of JNK, whe n compared with parental cells that were deficient in JNK activity, ha d increased c-jun and c-fos proteins. Finally, to show the relevance o f these observations in model systems, we studied blast cells from pat ients with Philadelphia chromosome-positive acute leukemic transformat ion, and observed comparable activities of JNK catalysis and c-jun/AP- 1 protein relative to the cell lines that possessed p210 BCR-ABL and J NK activity. These studies provide a basis for investigating the set o f downstream genes which augmented c-jun/AP-1 activity enlists in the process of transformation by p210 BCR-ABL. (C) 1998 by The American So ciety of Hematology.