ag-490 and Precursor-B-Cell-Lymphoblastic-Leukemia-Lymphoma

To investigate the relation of Jak3 constitutive activation and acute lymphoblastic leukemia(ALL).. NALM-6 cells were treated with varying concentrations of AG490, a Jak3 inhibitor. Apoptosis and proliferation of NALM-6 cells were tested by flow cytometry (FCM) analysis and MTT assay.. With the exception of AG490 5 mumol/L, the AG490 10, 15, 20 mumol/L induced a strong apoptotic response in NALM-6 cells by FCM analysis(P < 0.05) and significantly inhibited the proliferation of NALM-6 cells by MTT assay(P < 0.05). All of the effects were dose-dependent.. Jak3 inhibitor AG490 can inhibit proliferation and induce apoptosis in NALM-6 cells, and Jak3 activation is associated with pre-B ALL.

Topics: Antineoplastic Agents; Apoptosis; Humans; Janus Kinase 3; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein-Tyrosine Kinases; Tumor Cells, Cultured; Tyrphostins

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.

Topics: Antineoplastic Agents; Cell Division; Chromosomes, Human, Pair 11; DNA, Neoplasm; Dose-Response Relationship, Drug; Enzyme Inhibitors; Fusion Proteins, bcr-abl; Humans; Janus Kinase 2; Leukemia, Lymphoid; Philadelphia Chromosome; Phosphorylation; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Translocation, Genetic; Tumor Cells, Cultured; Tumor Stem Cell Assay; Tyrphostins