Phosphatidylinositol-3 kinase activity is regulated by BCR/ABL and is required for the growth of Philadelphia chromosome-positive cells

摘要: The BCR/ABL oncogenic tyrosine kinase is responsible for initiating and maintaining the leukemic phenotype of Philadelphia chromosome (Ph1)- positive cells. Phosphatidylinositol-3 (PI-3) known to interact with be activated by receptor nonreceptor kinases. We investigated whether PI-3 associates and/or regulated BCR/ABL, this interaction functionally significant Ph1 cell proliferation, and, if so, inhibition activity can exploited eliminate Ph1-positive cells from bone marrow. show that p85 alpha subunit transient expression in fibroblasts down-regulation using antisense oligodeoxynucleotides (ODNs) activates inhibits, respectively, enzymatic activity. use specific ODNs or constructs downregulate showed a requirement proliferation BCR/ABL-dependent lines chronic myelogenous leukemia (CML) primary Similarly, wortmannin, inhibitor p110 kinase, inhibited growth these normal marrow erythromyeloid, but not megakaryocyte, progenitors was [S]ODNs, at concentrations tested, did affect hematopoiesis. two BCR/ABL- factor-independent affected downregulation activity, confirming specificity observed effects on Thus, one downstream effectors CML Moreover, reverse transcriptase-polymerase chain reaction performed single colonies detect BCR-ABL transcripts wortmannin able selectively CML-blast crisis mixture