Activated mutants of the human gm-csf receptor β subunit cause myeloproliferative disorders and leukaemia in mice

To date several activating mutations have been discovered in the common βsubunit (hβc) of the receptors for human granulocytemacrophage colony stimulating (actor (GM-CSF), interleukin (IL)-3 and IL5, which enable it to signal in the absence of ligand. Two of these mutations, V449E and I374N, result in single arnino acid substitutions in the transmembrane and extracellular domains of hβc, respectively. A third, FIA, results in a 37 arnino acid duplication in the extracellular domain. We have shown previously that, when expressed in primary murine haemopoietic cells, the transmembrane mutant, V449E, could confer factor-independence on all cell types of the myeloid and erythroid compartments. However, the extracellular hβ_c mutants could confer factor independence on cells of the neutrophil and macrophage lineages only. We now believe this restriction reflects a requirement for the GM-CSF receptor oc subunit. In order to study the effects of hβ_c mutants in vivo, we have expressed all three mutants in the haemopoietic system of mice using retroviral transduction followed by bone marrow reconstitution. The transmembrane hβc mutant V449E induced an acute disorder, marked by blast cell accumulation in the blood and haemopoietic organs, which was reminiscent of AML. In contrast, the extracellular hβ_c mutants FIA and I374N induced chronic myeloproliferative disorders marked by elevated numbers of neutrophils, erythrocytes and platelets. Hence whilst activated hβ_c mutants are capable of inducing haemopoietic disorders, the type of disorder induced depends on the location of the activating mutation within hβc. Moreover, the in vitro effects of these mutant are not predictive of their in vivo effects; particularly surprising is the ability of the extracellular mutants to induce erythrocytosis A possible explanation is suggested by the ability of I374N to induce phosphorylation of the erythropoietin receptor in certain cell lines, in which this interaction can lead to factor-independent proliferation.