EXPRESSION OF ACTIVATED MUTANTS OF THE HUMAN INTERLEUKIN-3 INTERLEUKIN-5 GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR-RECEPTOR COMMON BETA-SUBUNIT IN PRIMARY HEMATOPOIETIC-CELLS INDUCES FACTOR-INDEPENDENT PROLIFERATION AND DIFFERENTIATION/

To date, several activating mutations have been discovered in the comm on signal-transducing subunit (h beta c) of the receptors for human gr anulocyte-macrophage colony-stimulating factor, interleukin-3, and int erleukin-5. Two of these, Fl Delta and 1374N, result in a 37 amino aci d duplication and a single amino acid substitution in the extracellula r domain of h beta c, respectively. A third, V449E, results in a singl e amino acid substitution in the transmembrane domain, Previous studie s comparing the activity of these mutants in different hematopoietic c ell lines imply that the transmembrane and extracellular mutations act by different mechanisms and suggest the requirement for cell type-spe cific molecules in signalling. To characterize the ability of these mu tant hpc subunits to mediate growth and differentiation of primary cel ls and hence investigate their oncogenic potential, we have expressed all three mutants in primary murine hematopoietic cells using retrovir al transduction. It is shown that, whereas expression of either extrac ellular hpc mutant confers factor-independent proliferation and differ entiation on cells of the neutrophil and monocyte lineages only, expre ssion of the transmembrane mutant does so on these lineages as well as the eosinophil, basophil, megakaryocyte, and erythroid lineages, Fact or-independent myeloid precursors expressing the transmembrane mutant display extended proliferation in liquid culture and in some cases yie lded immortalized cell lines. (C) 1997 by The American Society of Hema tology.