HIGH THROMBOPOIETIN PRODUCTION BY HEMATOPOIETIC-CELLS INDUCES A FATALMYELOPROLIFERATIVE SYNDROME IN MICE

To evaluate the effects of long-term, high-dose exposure to thrombopoi etin (TPO), lethally irradiated mice were grafted with bone marrow cel ls infected with a retrovirus carrying the murine TPO cDNA. Mice were studied for 10 months after transplantation. In plasma, TPO levels wer e highly elevated (10(4) U/mL) throughout the course of the study. All mice developed a lethal myeloproliferative disorder evolving in two s uccessive phases. During the first phase (7-9 weeks posttransplant), p latelet and white blood cell (WBC) counts rose four-and ten-fold, resp ectively, whereas hematocrits decreased slightly to 29% +/- 3%. The WB C were mainly mature granulocytes, but myeloid precursor cells were in variably observed as well as giant platelets with an irregular granule distribution. The striking features were a massive hyperplasia of meg akaryocytes and granulocytes in the spleen and bone marrow and a hypop lasia of erythroblasts in bone marrow. Total numbers of megakaryocyte colony-forming cell, burst-forming unit-erythroid, and granulocyte-mac rophage colony-forming cells were increased but colony-forming unit-er ythroid numbers decreased. From 10 weeks posttransplant and thereafter , WBC, platelets, and red blood cell numbers declined dramatically. Th e absolute numbers of progenitor cells were very low in the spleen and bone marrow, but sharply increased in the blood and peritoneal cavity . Extramedullary hematopoiesis was observed in several organs. Histolo gic sections of the spleen and bones revealed severe fibrosis and oste osclerosis. The mean survival time was 7 months posttransplant and mic e died with severe pancytopenia. Notably, two mice died between 3 and 4 months posttransplant with a leukemic transformation. This disorder was transplantable into secondary recipients who developed an attenuat ed form of the disease similar to the one previously described (Yan et al, Blood 86:4025, 1995). Taken together, our data show that high and persistent TPO production by transduced hematopoietic cells in mice r esults in a fatal myeloproliferative disorder that has a number of fea tures in common with human idiopathic myelofibrosis. (C) 1997 by The A merican Society of Hematology.