CONDITIONAL IMMORTALIZATION OF MOUSE MYELOMONOCYTIC, MEGAKARYOCYTIC AND MAST-CELL PROGENITORS BY THE HOX-2.4 HOMEOBOX GENE

Perkins, AC; Cory, S

Author(s): Perkins, AC; Cory, S;
Details: Publication Year 1993-10,Volume 12,Issue #10,Page 3835-3846
Journal Title: EMBO JOURNAL
Publication Type: Journal Article
Abstract: 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 tines 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.
Publisher: OXFORD UNIV PRESS UNITED KINGDOM
Keywords: HEMATOPOIETIC STEM-CELLS; GROWTH-FACTOR PRODUCTION; BONE-MARROW CULTURES; MULTI-CSF IL-3; MYELOID-LEUKEMIA; RETROVIRAL INSERTION; PRE-B; EXPRESSION; LINES; MURINE
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Creation Date: 1993-10-01 12:00:00