n4-(2-2-dimethyl-3-oxo-4h-pyrid(1-4)oxazin-6-yl)-5-fluoro-n2-(3-4-5-trimethoxyphenyl)-2-4-pyrimidinediamine and Leukemia

The nonreceptor protein spleen tyrosine kinase (Syk) is a key mediator of signal transduction in a variety of cell types, including B lymphocytes. We show that deregulated Syk activity allows growth factor-independent proliferation and transforms bone marrow-derived pre-B cells that are then able to induce leukemia in mice. Syk-transformed pre-B cells show a characteristic pattern of tyrosine phosphorylation, increased c-Myc expression, and defective differentiation. Treatment of Syk-transformed pre-B cells with a novel Syk-specific inhibitor (R406) reduces tyrosine phosphorylation and c-Myc expression. In addition, R406 treatment removes the developmental block and allows the differentiation of the Syk-transformed pre-B cells into immature B cells. Because R406 treatment also prevents the proliferation of c-Myc-transformed pre-B cells, our data indicate that endogenous Syk kinase activity may be required for the survival of pre-B cells transformed by other oncogenes. Collectively, our data suggest that Syk is a protooncogene involved in the transformation of lymphocytes, thus making Syk a potential target for the treatment of leukemia.

Topics: Adaptor Proteins, Signal Transducing; Adoptive Transfer; Animals; B-Lymphocytes; Benzamides; Cell Differentiation; Cell Line; Cell Proliferation; DNA-Binding Proteins; Fusion Proteins, bcr-abl; Humans; Imatinib Mesylate; Intercellular Signaling Peptides and Proteins; Intracellular Signaling Peptides and Proteins; Leukemia; Mice; Mice, Inbred BALB C; Mice, Knockout; Oxazines; Phospholipase C gamma; Phosphorylation; Piperazines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-myc; Pyridines; Pyrimidines; Receptors, Antigen, B-Cell; Spleen; Syk Kinase; Transfection