Novel murine myeloid cell lines that exhibit a differentiation switch in response to IL-3 or GM-CSF, or to different constitutively active mutants ofthe CM-CSF receptor beta subunit

Several activating mutations have recently been described in the common bet a subunit for the human interleukin(IL)-3, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors (h beta c), Two of these, FI Delta and 1374N, result, respectively, in a 37-amino acid duplication and a n isoleucine-to-asparagine substitution in the extracellular domain. A thir d, V449E, leads to valine-to-glutamic acid substitution in the transmembran e domain. Previous studies have shown that when expressed in murine hemopoi etic cells in vitro, the extracellular mutants can confer factor independen ce on only the granulocyte-macrophage lineage while the transmembrane mutan t can do so to all cell types of the myeloid and erythroid compartments. To further study the signaling properties of the constitutively active hpc mu tants, we have used novel murine hemopoietic cell lines, which we describe in this report. These lines, FDB1 and FDB2, proliferate in murine IL-3 and undergo granulocyte-macrophage differentiation in response to murine GM-CSF , We find that while the transmembrane mutant, V449E, confers factor-indepe ndent proliferation on these cell lines, the extracellular hpc mutants prom ote differentiation. Hence, in addition to their ability to confer factor i ndependence on distinct cell types, transmembrane and extracellular activat ed h beta c mutants deliver distinct signals to the same cell type. Thus, t he FDB cell lines, in combination with activated h beta c mutants, constitu te a powerful new system to distinguish between signals that determine hemo poietic proliferation or differentiation. (C) 2000 by The American Society of Hematology.