title: Primitive interleukin 3 null hematopoietic cells transduced with BCR-ABL show accelerated loss after culture of factor-independence in vitro and leukemogenic activity in vivo.
abstract: Primitive chronic myeloid leukemia cells display a unique autocrine interleukin 3 (IL-3)/granulocyte-colony-stimluating factor (G-CSF) mechanism that may explain their abnormal proliferation and differentiation control. Here we show that BCR-ABL transduction of primitive Sca-1(+) lin(-) mouse bone marrow (BM) cells causes immediate activation of IL-3, G-CSF, and granulocyte macrophage-colony-stimulating factor (GM-CSF) expression in these cells. Their autocrine IL-3-mediated growth dependence is thus demonstrable only in clonal cultures where paracrine effects are reduced. Interestingly, upon continued culture, these cells produce large populations of rapidly proliferating mast cells in which only the IL-3 autocrine mechanism is consistently maintained, together with evidence of hyperphosphorylation of p210(BCR-ABL) and STAT5 and retention of a multilineage but attenuated in vivo leukemogenic potential characterized by a prolonged latency. BCR-ABL transduction of IL-3(-/-) Sca-1(+) lin(-) BM cells initially activates GM-CSF and G-CSF production, factor independence, and the ability to generate phenotypically indistinguishable populations of mast cells. However, maintenance of factor independence, and p210(BCR-ABL) and STAT 5 activation beyond 4 to 6 weeks, requires rescue with an IL-3 transgene. The cultured BCR-ABL-transduced IL-3(-/-) cells also lack leukemogenic activity in vivo. These findings provide new evidence that IL-3 production is a rapid, sustained, and biologically relevant consequence of BCR-ABL expression in primitive hematopoietic cells with multilineage leukemogenic activity.
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, and the Department of Medicine, Laboratory Medicine, and Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Jiang
authors.forename: Eddy
authors.initials: E
authors.lastname: Ng
authors.forename: Calvin
authors.initials: C
authors.lastname: Yip
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Eisterer
authors.forename: Yves
authors.initials: Y
authors.lastname: Chalandon
authors.forename: Matthew
authors.initials: M
authors.lastname: Stuible
authors.forename: Allen
authors.initials: A
authors.lastname: Eaves
authors.forename: Connie J
authors.initials: CJ
authors.lastname: Eaves
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D018929:Cell Culture Techniques; D002455:Cell Division / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000502:physiology*; D016179:Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D007377:Interleukin-3 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D007938:Leukemia / Q000209:etiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D014161:Transduction, Genetic
chemical_list: D007377:Interleukin-3; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016044:Fusion Proteins, bcr-abl