The preleukemic state of mice reconstituted with Mixl1-transduced marrow cells.
Murine granulocytic cells, in becoming leukemic, need to acquire enhanced self-generation and a capacity for autocrine growth stimulation. Mice transplanted with bone marrow cells transduced with the Mixl1 homeobox gene develop a very high frequency of myeloid leukemia derived from the transduced cells. Preleukemic mice contained a high frequency of transduced clonogenic granulocytic cells. They exhibited an abnormally high capacity for self-replication and could generate immortalized granulocytic cell lines that remained absolutely dependent on either GM-CSF or IL-3 and were not leukemic. Organs from mice repopulated by marrow cells transduced either with Mixl1 or the control murine stem cell virus vector exhibited a capacity to produce IL-3 in vitro, activity being highest with the lungs, marrow, bladder, and thymus. Supporting evidence for the in vivo production of IL-3 was the frequent development of mast cells in the marrow. Overexpression of Mixl1 appears capable of inducing an abnormal self-renewal capacity in granulocytic precursors. Aberrant production of IL-3 was not present in the continuous Mixl cell lines and was therefore not in itself likely to be a leukemogenic change but it could support the enhanced survival and proliferation of the Mixl1 granulocytic populations until a final leukemogenic mutation occurs in them.
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia. metcalf@wehi.edu.au
Donald
D
Metcalf
Stefan
S
Glaser
Sandra
S
Mifsud
Ladina
L
Di Rago
Lorraine
L
Robb
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D002478:Cells, Cultured; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007377:Interleukin-3 / Q000096:biosynthesis; D008407:Mast Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011289:Preleukemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*
D018398:Homeodomain Proteins; D007377:Interleukin-3; C464781:Mixl1 protein, mouse