fti-277 and Precursor-B-Cell-Lymphoblastic-Leukemia-Lymphoma

The v-Abl tyrosine kinase activates several signaling pathways during transformation of bone marrow cells in mice. Because the SH2-containing inositol 5'-phosphatase (SHIP) and Downstream of tyrosine kinase 1 (Dok1) have been shown to interact with Abl, the effect of SHIP and Dok1 deficiency on v-Abl transformation was investigated. Bone marrow cells from either Dok1- or SHIP-deficient mice are more susceptible to transformation by v-Abl. v-Abl-transformed preB cells from these knockout mice show Abl kinase-dependent hyperproliferation and moderate resistance to apoptosis. Elevated activation of Ras, Raf-1, and Erk, but not of Akt, was observed in either SHIP(-/-) or Dok1(-/-) v-Abl-transformed cells. This activation is sensitive to treatment with STI571. Furthermore, treatment of these cells with either a farnesyltransferase inhibitor or a MEK1/2 inhibitor abrogates the increased proliferation of SHIP(-/-) or Dok1(-/-) cells in a dose-dependent manner. Complementation of SHIP(-/-) or Dok1(-/-) cells abrogates their hyperproliferation and intracellular Erk activation. These data indicate that both SHIP and Dok1 functionally regulate the activation of Ras-Erk pathway by v-Abl and affect the mitogenic activity of v-Abl transformed bone marrow cells.

Topics: Animals; Apoptosis; Benzamides; Bone Marrow Cells; Cell Line; Cell Proliferation; Cell Transformation, Neoplastic; DNA-Binding Proteins; Dose-Response Relationship, Drug; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Farnesyltranstransferase; Gene Expression Regulation, Leukemic; Imatinib Mesylate; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Methionine; Mice; Oncogene Proteins v-abl; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; Phosphoproteins; Phosphoric Monoester Hydrolases; Piperazines; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Pyrimidines; ras Proteins; RNA-Binding Proteins; Signal Transduction