Altered tyrosine phosphor ylation of jak1 and stat1 proteins in 32d cells overexpressing p210^bcr-abi- oncoprotein

JAK kinases participate and play a critical role in cellular responses to a large array of cytokines and growth factors in mammalian hematopoietic cells. An activating point mutation in JAK kinases causes a leukemia-like hematopoietic abnormality in drosophila. The leukemogenic p21^bcr-abl oncoprotein, which contains multiple protein-protein interaction domains, phosphorylates a number of cellular proteins through remarkably enhanced tyrosine kinase activity, upon which its transforming properties depend. Chronic myelogenous leukemia cells, which express this chimeric protein, exhibit not only unregulated proliferation of mature myeloid cells and protection against programmed cell death, but also altered responses to cytokines, indicating that p210^bcr-abl' transforming protein may crosstalk to JAK-STAT pathway. In order to test if the presence of p2K^bcr-abl kinase affected the JAK-STAT pathway, we stably transfected a variant of the 32D mouse myeloid leukemia cell line with a cDNA for the human p210^bcr-abl oncoprotein. Phosphorylation of JAK1 kinase was detected to a much greater degree in 32D cells overexpressing the p2106°^bcr-abl hybrid protein than was the case in the parental 32D cell line. In contrast, no phosphorylation of the JAK2 kinase, a member of JAK family, was observed in 32D cells either in the presence or absence of the p210^bcr-abl protein. However, STAT1, a substrate of JAK1, was found to be phosphorylated at an increased level in 32D cells containing overexpressed pll10^bcr-abl fusion protein. These results indicate that the p210^bcr-abl chimera may alter the regulation of the phosphorylation and activation of the JAK1 kinase STAT1 pathway.