Nonneoplastic hematopoietic myeloproliferative syndrome induced by dysregulated multi-CSF (IL-3) expression.
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.
Chang
J M
JM
Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
Metcalf
D
D
Lang
R A
RA
Gonda
T J
TJ
Johnson
G R
GR
D000818:Animals; D016026:Bone Marrow Transplantation; D003001:Cloning, Molecular; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000473:pathology / Q000502:physiology; D006413:Hematopoietic System / Q000473:pathology; D007377:Interleukin-3 / Q000502:physiology*; D051379:Mice; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000473:pathology; D014162:Transfection
D007377:Interleukin-3