title: Progressive changes in the leukemogenic signaling in BCR/ABL-transformed cells.
abstract: Our previous study indicated that BCR/ABL SH2 domain and BCR/ABL SH3 domain+SH2 domain complex are required for immediate activation of the phosphatidylinositol-3 kinase PI-3k)--> Akt serine/threonine kinase pathway and of the signal transducer and activator of transcription 5 (STAT5), respectively, in hematopoietic cells. We show here that the defect in activation of PI-3k/Akt by BCR/ABL DeltaSH2 mutant (SH2 domain deleted) and of STAT5 by BCR/ABL DeltaSH3+DeltaSH2 mutant (SH3 and SH2 domains deleted) is not permanent and both Akt and STAT5 could be 're-activated' by in vitro culture. This phenomenon was responsible for increased resistance to apoptosis, growth factor-independent proliferation and leukemogenesis in SCID mice. Incubation of cells with BCR/ABL tyrosine kinase inhibitor STI571 abrogated the 're-activation' of Akt or STAT5 by BCR/ABL SH3+SH2 mutants in some clones, in the others Akt and STAT5 activation became independent on BCR/ABL kinase activity. The immediate upstream activators of Akt and STAT5 such as PI-3k and Jak-2 were also activated. In addition, the common beta subunit of IL-3/IL-5/GM-CSF receptor was tyrosine phosphorylated in the clones in which 're-activation' was dependent on the BCR/ABL kinase activity. These results suggested that 're-activation' of Akt and STAT5, in the absence of functional BCR/ABL SH3+SH2 domains, may be achieved by two different mechanisms: (i) BCR/ABL kinase-dependent activation of alternative pathway(s) and (ii) additional genetic changes stimulating Akt and STAT5 independently of BCR/ABL. Oncogene (2000) 19, 4117 - 4124
authors.affiliation: Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, PA 19122, USA.
authors.forename: M
authors.initials: M
authors.lastname: Nieborowska-Skorska
authors.forename: A
authors.initials: A
authors.lastname: Slupianek
authors.forename: T
authors.initials: T
authors.lastname: Skorski
mesh_terms: D000818:Animals; D017209:Apoptosis; D002461:Cell Line, Transformed; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D053614:Janus Kinase 2; D007951:Leukemia, Myeloid; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction; D018909:src Homology Domains
chemical_list: D016044:Fusion Proteins, bcr-abl; D053614:Janus Kinase 2; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; C507926:Jak2 protein, mouse