Pronounced thrombocytosis in transgenic mice expressing reduced levels of Mpl in platelets and terminally differentiated megakaryocytes

Abstract

We generated mice expressing a full-length Mpl transgene under the control of a 2-kb Mpl promoter in an Mpl-/-background, effectively obtaining mice that express full-length Mpl in the absence of other Mpl isoforms. These mice developed thrombocytosis with platelet levels approximately 5-fold higher than wild-type controls and markedly increased megakaryocyte numbers. The reintroduc-tion of one wild-type Mpl allele restored normal platelet counts. We excluded the deletion of Mpl-tr, a dominant-negative isoform, as the underlying molecular cause for thrombocytosis. Instead, we found that transgene expression driven by the 2-kb Mpl promoter fragment was decreased during late megakaryocyte maturation, resulting in strongly diminished Mpl protein expression in platelets. Because platelets exert a negative feedback on thrombopoiesis by binding and consuming Tpo in the circulation through Mpl, we propose that the severe reduction of Mpl protein in platelets in Mpl-transgenic Mpl-/- mice shifts the equilibrium of this feedback loop, resulting in markedly elevated levels of megakaryo-cytes and platelets at steady state. Although the mechanism causing decreased expression of Mpl protein in platelets from patients with myeloprolif-erative disorders differs from this trans-genic model, our results suggest that lowering Mpl protein in platelets could contribute to raising the platelet count. © 2009 by The American Society of Hematology.