STAT3 is constitutively active in some patients with Polycythemia rubra vera

Objective. Polycythemia vera is a clonal stem cell disorder characterized b y hyperproliferation of the erythroid, myeloid, and megakaryocytic lineages , While it has been shown that progenitor cells of P. vera patients are hyp ersensitive to several growth factors including erythropoietin, insulin-lik e growth factor-1, thrombopoietin, interleukin-3, and granulocyte/monocyte colony-stimulating factor, the molecular pathogenesis of this disease remai ns unknown. Growth factor hypersensitivity could be mediated by changes in signal transduction pathways, We therefore investigated a common downstream effector of cytokines, the signal transducers and activators of transcript ion (STATs), A constitutive activation of STAT factors could explain the in creased proliferation of P. vera cells even in the absence of growth factor stimulation. Methods. Peripheral granulocytes from patients with P. vera and from health y volunteers were assayed for STAT1, 3, and 5 DNA binding by electrophoreti c mobility shift assay. Results. Four of 14 P. vera patients analyzed showed constitutive STAT3 DNA binding in unstimulated peripheral granulocytes, while none of the 17 heal thy volunteers tested did. None of the subjects showed constitutive STAT1 o r STETS activity, Western blotting demonstrated that, in the three patients , STAT3 is constitutively phosphorylated on Tyr 705, whereas it is unphosph orylated in the other patients and in controls. Interestingly, constitutive STAT3 activity did not correlate with the duration of disease or the treat ment regimen. It was observed in a recently diagnosed patient and in two pa tients treated only with phlebotomy. Conclusion. Our data suggest that constitutive phosphorylation and activati on of STAT3 is not a secondary event induced by mutagenizing agents or by p rolonged hyperproliferation of hematopoietic cells, but rather represents a primary molecular aberration. Constitutively active STAT3 may contribute t o the growth factor hypersensitivity of P. vera cells. (C) 2001 Internation al Society for Experimental Hematology. Published by Elsevier Science Inc.