title: The JAK2 inhibitor AG490 predominantly abrogates the growth of human B-precursor leukemic cells with 11q23 translocation or Philadelphia chromosome.
abstract: The Janus kinase (JAK) family is one of intracellular protein tyrosine kinases (PTKs) present in hematopoietic and lymphoid cells and has been shown to 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 performed. In the present study, we tested 16 human lymphoid leukemic cell lines (B-precursor, 12; T cell, four) for their sensitivity to AG490 using 3H-thymidine incorporation and colony formation assays, and found that B-precursor cell lines with 11q23 translocation or Philadelphia chromosome (Ph1) whose JAK2 proved to be constitutively phosphorylated were predominantly sensitive to AG490 at a concentration that has few inhibitory effect on normal hematopoiesis. We first revealed the association of JAK2 with BCR-ABL in Ph1-positive cell lines and with Bruton's tyrosine kinase (BTK) in cell lines with 11q23 translocation by coimmunoprecipitation experiments. Of interest, AG490 markedly down-regulated phosphorylation of JAK2, but rather transiently up-regulated phosphorylation of BCR-ABL and BTK, suggesting direct implication of AG490 in the process of the JAK2 dephosphorylation. These results indicate that AG490 exerts a potent inhibitory activity to B-precursor leukemia with specific chromosomal abnormalities, and a therapeutic approach using AG490 is expected.
authors.affiliation: Department of Pediatrics, Yamanashi Medical University, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Miyamoto
authors.forename: K
authors.initials: K
authors.lastname: Sugita
authors.forename: K
authors.initials: K
authors.lastname: Goi
authors.forename: T
authors.initials: T
authors.lastname: Inukai
authors.forename: K
authors.initials: K
authors.lastname: Lijima
authors.forename: T
authors.initials: T
authors.lastname: Tezuka
authors.forename: S
authors.initials: S
authors.lastname: Kojika
authors.forename: M
authors.initials: M
authors.lastname: Nakamura
authors.forename: K
authors.initials: K
authors.lastname: Kagami
authors.forename: S
authors.initials: S
authors.lastname: Nakazawa
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002880:Chromosomes, Human, Pair 11; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2; D007945:Leukemia, Lymphoid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010677:Philadelphia Chromosome; D010766:Phosphorylation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D020032:Tyrphostins / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C069028:AG 127; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C507924:JAK2 protein, human; D053614:Janus Kinase 2