CHRONIC EXPOSURE TO RETROVIRAL VECTOR ENCODED MGDF (MPL-LIGAND) INDUCES LINEAGE-SPECIFIC GROWTH AND DIFFERENTIATION OF MEGAKARYOCYTES IN MICE

Megakaryocyte growth and development factor (MGDF) has recently been i dentified as a ligand for the c-mpl receptor. Using retroviral-mediate d gene transfer, MGDF has been overexpressed in mice to evaluate the s ystematic effects due to chronic exposure to this growth factor. MGDF overexpressing mice had more rapid platelet recovery than control mice after transplantation. Following this recovery, the platelet levels c ontinued increasing to fourfold to eightfold above normal baseline lev els and remained elevated (fivefold above control mice) in these anima ls, which are alive and well at more than 4 months posttransplantation . Increased megakaryocyte numbers were detected in a number of organs in these mice including bone marrow, spleen, liver, and lymph nodes. P rolonged overexpression of MGDF led to decreased marrow hematopoiesis, especially erythropoiesis, with a shift to extramedullary hematopoies is in the spleen and liver. All the MGDF overexpressing mice analyzed to date developed myelofibrosis and osteosclerosis, possibly induced b y megakaryocyte and platelet produced cytokines. No significant effect on other hematopoietic lineages was seen in the MGDF overexpressing m ice, showing that the stimulatory effect of MGDF in vivo is restricted to the megakaryocyte lineage. (C) 1995 by The American Society of Hem atology.