Overexpression in Animal Models

TPO barely remained detectable in the preceding experiment, amounts of TPO were persistently high in these mice during the entire course of the experiment. Early after transplantation, platelet and white blood cell counts increased, and hematocrits decreased. Megakaryocytes and granulocytes and their respective progenitor cells were markedly increased in the spleen, but erythroblasts and their precursor cells were decreased in the marrow. Later, the number of progenitor cells in the spleen decreased, extramedullary hematopoiesis was seen, the marrow and spleen developed marked fibrosis, and the bones developed osteosclerosis. The mice had reduced survival, and some developed leukemia (85).

In a third model, normal mice and syngeneic mice with variable degrees of immune dysfunction (nude, SCID, NOD/SCID) were infected with adenovectors carrying human TPO cDNA. All mice had an increase in platelet count, but the increase was much higher in the SCID (T- and B-cell defect, minimal Ab response) and NOD/SCID (T- and B-cell defect, minimal Ab response, mononuclear phagocytes diminished in number and function) mice than in BALB/c (control) or nude mice (T-cell defect, impaired Ab production). The platelet count increase was proportional to the concentration of circulating TPO. The control mice subsequently developed Abs to human TPO that crossreacted with murine TPO, and the mice became thrombocy-topenic. The SCID and NOD/SCID continued to express high concentration of TPO and did not develop Abs. They both developed hypercellular bone marrows; however, only the SCID mice developed osteosclerosis, myelofibrosis, and extramedullary hematopoiesis (86).

These results suggest that chronic overexpression of low amounts of TPO in normal animals leads to thrombocytosis, marrow fibrosis, and osteosclerosis that mimics the human disorder of agnogenic myelofibrosis with myeloid metaplasia. With higher chronic expression, such changes may evolve into more significant fibrosis and possibly leukemic transformation. The fibrosis is not entirely mediated by TPO or the increased megakaryocyte mass but requires concomitant functional mono-cytes and/or macrophages.

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