Conditional immortalization of mouse myelomonocytic, megakaryocytic and mast cell progenitors by the Hox-2.4 homeobox gene.
The murine myelomonocytic cell line WEHI-3B exhibits ectopic expression of the genes encoding the homeobox protein, Hox-2.4, and the myeloid growth factor, interleukin-3 (IL-3). We showed previously that concomitant expression of IL-3 and Hox-2.4 in bone marrow cells induced the development of transplantable growth factor-independent tumours resembling the WEHI-3B tumour. We have now investigated the effect of enforced expression of Hox-2.4 alone. Bone marrow cells were infected with Hox-2.4 retrovirus and then either cultured in agar or transplanted into irradiated mice. In vitro, colonies derived from virus-infected cells readily yielded IL-3-dependent, non-tumorigenic cell lines of the myelomonocytic, megakaryocytic and mast cell lineages. Surprisingly, both the establishment and maintenance of these lines required very high concentrations of IL-3 and reduced levels promoted differentiation. Transplanted mice analysed after 3 months appeared normal but their spleen and bone marrow contained abundant provirus-bearing progenitor cells, from which IL-3-dependent long-term cell lines could readily be established in vitro. Four of 18 animals monitored for up to 12 months eventually developed clonal leukaemia, associated in three cases with IL-3 production. Thus ectopic expression of Hox-2.4 enhances self-renewal of immature myeloid progenitors and progression to a fully malignant state is favoured by somatic mutations conferring autocrine production of IL-3.
Perkins
A C
AC
Walter and Eliza Hall Institute of Medical Research, Australia.
Cory
S
S
D000818:Animals; D001854:Bone Marrow Cells; D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism; D005801:Genes, Homeobox; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D018398:Homeodomain Proteins; D007377:Interleukin-3 / Q000235:genetics / Q000502:physiology; D007938:Leukemia / Q000235:genetics*; D008407:Mast Cells / Q000166:cytology; D008533:Megakaryocytes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009000:Monocytes / Q000166:cytology; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000502:physiology; D016185:Receptors, Interleukin-3 / Q000378:metabolism
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C095822:Hoxb8 protein, mouse; D007377:Interleukin-3; D009363:Neoplasm Proteins; D016185:Receptors, Interleukin-3