Da. Frank et L. Varticovski, BCR ABL LEADS TO THE CONSTITUTIVE ACTIVATION OF STAT PROTEINS, AND SHARES AN EPITOPE WITH TYROSINE-PHOSPHORYLATED STATS/, Leukemia, 10(11), 1996, pp. 1724-1730
The mechanism by which BCR/abl leads to the transformation of hematopo
ietic cells is not understood. The introduction of BCR/abl into BaF3 c
ells, an IL-3-dependent pro-lymphocytic cell line, abrogates the requi
rement of IL-3 for growth, Given that IL-3 leads to the phosphorylatio
n of Stat proteins, we tested the hypothesis that BCR/abl transformati
on of hematopoietic cells induces the phosphorylation of Stats. We fou
nd that BaF3 cells transformed by either the p190 or p210 forms of BCR
/abl possess constitutively phosphorylated Stat1 and Stat5. Phosphoryl
ation of Stat proteins was greater in cells transformed by p190 BCR/ab
l than in cells transformed by p210 BCR/abl, suggesting that the magni
tude of phosphorylation of Stat, proteins may play a role in the, biol
ogical effects of BCR/abl. Expression of BCR/abl containing a mutation
(Y177F) that prevents its interaction with GRB2 led to a decrease in
the phosphorylation of Stat1 and Stat5. This suggested that GRB2, or i
ts binding site on BCR/abl, may participate in the phosphorylation of
Stat proteins. We also observed that the antiphospho-Stat antibody dir
ectly recognized both the p190 and p210 forms of BCR/abl. This indicat
ed that a tyrosine residue that becomes phosphorylated in BCR/abl may
share homology with the tyrosine phosphorylation site of Stat1 and Sta
t5. These findings may have implications for the mechanisms by which B
CR/abl interacts with signaling pathways to confer growth factor indep
endence and induce transformation of hematopoietic cells.