Post 5-fluorouracil-treated murine marrow cells were infected with a retroviral vector (MPZen) bearing a multi-potential colony stimulating factor (Multi-CSF) cDNA insert and then transplanted into lethally irradiated syngeneic recipients to study the effects of autocrine production of Multi-CSF in normal hematopoietic cells. Extremely high levels (14,000 U/mL) of Multi-CSF were detected in the sera and in media conditioned by various hematopoietic tissues of the transplanted animals. While spleen, peritoneal, and peripheral blood cellularity increased approximately 10-fold, 10-fold, and 50-fold, respectively, bone marrow cellularity decreased twofold. Progenitor numbers were depressed twofold in the bone marrow but elevated more than 100-fold in the spleen and peritoneum. The majority (80%) of transplanted mice died within 5 weeks of transplantation and showed extensive neutrophilic infiltration of the spleen, lung, liver, and muscle, often with mast cell foci; a phenomenon also seen in the skin and intestine. Neither the infected cells from hematopoietic tissues of the primary mice, nor autonomous mast cell-lines that grew from these cells in liquid culture produced any overt disease when transplanted into normal or sublethally irradiated secondary recipients. In contrast, injection into mice of autonomous FDC-P1 cells transformed by the same retroviral construct led to tumor formation in vivo within 4 weeks. Thus, dysregulated Multi-CSF expression by normal hematopoietic cells produces a fatal but nonneoplastic myeloproliferative syndrome.