The JAK2 inhibitor AG490 predominantly abrogates the growth of human B-precursor leukemic cells with 11q23 translocation or Philadelphia chromosome

The Janus kinase (JAK) family is one of intracellular protein tyrosine kina ses (PTKs) present in hematopoietic and lymphoid cells and has been shown t o play a crucial role in a variety of biological responses. It was reported that a human B-precursor leukemic cell line was potently inhibited in its proliferation by one of synthetic PTK inhibitors (tyrphostins), AG490, via anti-JAK2 activity. However, no extensive studies about it have been perfor med. In the present study, we tested 16 human lymphoid leukemic cell lines (B-precursor, 12; T cell, four) for their sensitivity to AG490 using IH-thy midine incorporation and colony formation assays, and found that B-precurso r cell lines with 11q23 translocation or Philadelphia chromosome (Phl) whos e JAK2 proved to be constitutively phosphorylated were predominantly sensit ive to AG490 at a concentration that has few inhibitory effect on normal he matopoiesis. We first revealed the association of JAK2 with BCR-ABL in Phl- positive cell lines and with Bruton's tyrosine kinase (BTK) in cell lines w ith 11q23 translocation by coimmunoprecipitation experiments. Of interest, AG490 markedly down-regulated phosphorylation of JAK2, but rather transient ly up-regulated phosphorylation of BCR-ABL and BTK, suggesting direct Impli cation of AG490 in the process of the JAK2 dephosphorylation. These results indicate that AG490 exerts a potent inhibitory activity to B-precursor leu kemia with specific chromosomal abnormalities, and a therapeutic approach u sing AG490 is expected.