title: Sequential mutations in the interleukin-3 (IL3)/granulocyte-macrophage colony-stimulating factor/IL5 receptor beta-subunit genes are necessary for the complete conversion to growth autonomy mediated by a truncated beta C subunit.
abstract: An amino-terminally truncated beta C receptor (beta C-R) subunit of the interleukin-3 (IL3)/granulocyte-macrophage colony-stimulating factor/IL5 receptor complex mediates factor-independent and tumorigenic growth in two spontaneous mutants of a promyelocytic cell line. The constitutive activation of the JAK2 protein kinase in these mutants confirms that signaling occurs through the truncated receptor protein. Noteworthily, in addition to a 10-kb deletion in the beta C-R subunit gene encoding the truncated receptor, several secondary and independent mutations that result in the deletion or functional inactivation of the allelic beta C-R subunit and the closely related beta IL3-R subunit genes were observed in both mutants, suggesting that such mutations are necessary for the full oncogenic penetrance of the truncated beta C-R subunit. Reversion of these mutations by the expression of the wild-type beta C-R in the two mutants resulted in a fivefold decrease in cloning efficiency of the mutants in the absence of IL3, confirming a functional interaction between the wild-type and truncated proteins. Furthermore, expression of the truncated beta C-R subunit in factor-dependent myeloid cells did not immediately render the cells autonomous but increased the spontaneous frequency to factor-independent growth by 4 orders of magnitude. Implications for both leukemogenic progression and receptor-subunit interaction and signaling are discussed.
authors.affiliation: Abteilung der Zell- und Virusgenetik, Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie, Hamburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Hannemann
authors.forename: T
authors.initials: T
authors.lastname: Hara
authors.forename: M
authors.initials: M
authors.lastname: Kawai
authors.forename: A
authors.initials: A
authors.lastname: Miyajima
authors.forename: W
authors.initials: W
authors.lastname: Ostertag
authors.forename: C
authors.initials: C
authors.lastname: Stocking
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D005091:Exons; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D006410:Hematopoiesis / Q000235:genetics; D007377:Interleukin-3 / Q000235:genetics*; D007438:Introns; D053614:Janus Kinase 2; D007942:Leukemia, Experimental / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D018123:Receptors, Interleukin / Q000235:genetics*; D053649:Receptors, Interleukin-5; D017384:Sequence Deletion; D014407:Tumor Cells, Cultured
chemical_list: D018076:DNA, Complementary; D007377:Interleukin-3; D011518:Proto-Oncogene Proteins; D018123:Receptors, Interleukin; D053649:Receptors, Interleukin-5; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2