PROGENITOR-CELL HYPERPLASIA WITH RARE DEVELOPMENT OF MYELOID-LEUKEMIAIN INTERLEUKIN-11 BONE-MARROW CHIMERAS

Post 5-fluorouracil-treated murine bone marrow cells infected with a r ecombinant retrovirus (murine stem cell virus-interleukin 11 [MSCV-IL- 11]) bearing a human IL-11 gene were transplanted into lethally irradi ated syngeneic mice. Analysis of proviral integration sites in DNA pre pared from hematopoietic tissues and purified cell populations of long -term reconstituted primary and secondary recipients demonstrated poly clonal engraftment by multipotential stem cells. High levels (100-1,50 0 U/ml) of IL-11 were detected in the plasma of the MSCV-IL-11 mice. S ystemic effects of chronic IL-11 exposure included loss of body fat, t hymus atrophy, some alterations in plasma protein levels, frequent inf lammation of the eyelids, and often a hyperactive state. A sustained r ise in peripheral platelet levels (approximately 1.5-fold) was seen th roughout the observation period (4-17 wk). No changes were observed in the total number of circulating leukocytes in the majority of the tra nsplanted animals (including 10 primary and 18 secondary recipients) d espite a >20-fold elevation in myeloid progenitor cell content in the spleen. The exceptions were members of one transplant pedigree which p resented with myeloid leukemia during the secondary transplant phase. A clonal origin of the disease was determined, with significant expans ion of the MSCV-IL-11-marked clone having occurred in the spleen of th e primary host. Culturing of leukemic spleen cells from a quaternary r ecipient led to the establishment of a permanent cell line (denoted PG MD1). IL-11-producing PGMD1 myeloid leukemic cells are dependent on IL -3 for continuous growth in vitro and they differentiate into granuloc ytes and macrophages in response to granulocyte/macrophage colony-stim ulating factor. The inability of autogenously produced IL-11 to suppor t autonomous growth of PGMD1 cells argues against a mechanism of trans formation involving a classical autocrine loop.