Progenitor cell hyperplasia with rare development of myeloid leukemia in interleukin 11 bone marrow chimeras.
Post 5-fluorouracil-treated murine bone marrow cells infected with a recombinant retrovirus (murine stem cell virus-interleukin 11 [MSCV-IL-11]) bearing a human IL-11 gene were transplanted into lethally irradiated syngeneic mice. Analysis of proviral integration sites in DNA prepared from hematopoietic tissues and purified cell populations of long-term reconstituted primary and secondary recipients demonstrated polyclonal engraftment by multipotential stem cells. High levels (100-1,500 U/ml) of IL-11 were detected in the plasma of the MSCV-IL-11 mice. Systemic effects of chronic IL-11 exposure included loss of body fat, thymus atrophy, some alterations in plasma protein levels, frequent inflammation of the eyelids, and often a hyperactive state. A sustained rise in peripheral platelet levels (approximately 1.5-fold) was seen throughout the observation period (4-17 wk). No changes were observed in the total number of circulating leukocytes in the majority of the transplanted animals (including 10 primary and 18 secondary recipients) despite a > 20-fold elevation in myeloid progenitor cell content in the spleen. The exceptions were members of one transplant pedigree which presented with myeloid leukemia during the secondary transplant phase. A clonal origin of the disease was determined, with significant expansion of the MSCV-IL-11-marked clone having occurred in the spleen of the primary host. Culturing of leukemic spleen cells from a quaternary recipient led to the establishment of a permanent cell line (denoted PGMD1). IL-11-producing PGMD1 myeloid leukemic cells are dependent on IL-3 for continuous growth in vitro and they differentiate into granulocytes and macrophages in response to granulocyte/macrophage colony-stimulating factor. The inability of autogenously produced IL-11 to support autonomous growth of PGMD1 cells argues against a mechanism of transformation involving a classical autocrine loop.
Hawley
R G
RG
Division of Cancer Research, Sunnybrook Health Science Centre, Toronto, Ontario, Canada.
Fong
A Z
AZ
Ngan
B Y
BY
de Lanux
V M
VM
Clark
S C
SC
Hawley
T S
TS
D000818:Animals; D001402:B-Lymphocytes / Q000382:microbiology; D001853:Bone Marrow / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D016026:Bone Marrow Transplantation; D002678:Chimera; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000382:microbiology / Q000473:pathology*; D006801:Humans; D006965:Hyperplasia; D017370:Interleukin-11 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015850:Interleukin-6 / Q000502:physiology; D007951:Leukemia, Myeloid / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010976:Platelet Count; D012190:Retroviridae / Q000235:genetics
D017370:Interleukin-11; D015850:Interleukin-6