A non-functioning vitamin D receptor predisposes to leukaemoid reactions in mice

The vitamin D hormone 1,25-dihydroxyvitamin D(3) [1,25(OH)(2) D(3) ], the biologically active form of vitamin D, is not only essential for mineral metabolism but may have important functions beyond calcium homoeostasis. By gene targeting, we have recently generated mice expressing a functionally inactive mutant vitamin D receptor (VDR). After a change in environmental conditions from specific pathogen free (SPF) conditions to a modified barrier system, a high percentage of aged mutant, but not wild-type, mice developed a haematological disorder characterized by splenomegaly, granulocytosis, thrombocytosis and dysplastic changes with displacement of erythropoiesis in bone marrow during the following months. All cases were associated with very high serum levels of the acute phase reaction protein serum amyloid A (SAA). Serological testing of affected mice revealed antibodies against murine hepatitis virus (MHV). However, electron microscopy of spleen and bone marrow cells did not reveal virus particles, and clinical signs of infectious diseases were absent. We hypothesize that a non-functioning VDR is associated with a latent defect in the regulation of myeloid cell differentiation and proliferation. Under the conditions of environmental stress, this latent defect may predispose to a deregulation of myelopoiesis in the form of a leukaemoid reaction accompanied by dysplastic changes. Thus, 1,25(OH)(2) D(3) may be an important inhibitory factor in the onset and progression of myeloproliferative and myelodysplastic diseases.