Inactivation of PU.1 in adult mice leads to the development of myeloid leukemia.
Genetically primed adult C57BL mice were deleted of exon 5 of the gene encoding the transcription factor PU.1 by IFN activation of Cre recombinase. After a 13-week delay, conditionally deleted (PU.1(-/-)) mice began dying of myeloid leukemia, and 95% of the mice surviving from early postinduction death developed transplantable myeloid leukemia whose cells were deleted of PU.1 and uniformly Gr-1 positive. The leukemic cells formed autonomous colonies in semisolid culture with varying clonal efficiency, but colony formation was enhanced by IL-3 and sometimes by granulocyte-macrophage colony-stimulating factor. Nine of 13 tumors analyzed had developed a capacity for autocrine IL-3 or granulocyte-macrophage colony-stimulating factor production, and there was evidence of rearrangement of the IL-3 gene. Acquisition of autocrine growth-factor production and autonomous growth appeared to be major events in the transformation of conditionally deleted PU.1(-/-) cells to fully developed myeloid leukemic populations.
Metcalf
Donald
D
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3050, Victoria, Australia. metcalf@wehi.edu.au
Dakic
Aleksandar
A
Mifsud
Sandra
S
Di Rago
Ladina
L
Wu
Li
L
Nutt
Stephen
S
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D045744:Cell Line, Tumor; D017690:Cell Transplantation; D005434:Flow Cytometry; D017353:Gene Deletion; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006133:Growth Substances / Q000378:metabolism; D007377:Interleukin-3 / Q000378:metabolism; D007938:Leukemia / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology*; D013154:Spleen / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology*; D000099232:Proto-Oncogene Protein Spi-1
D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006133:Growth Substances; D007377:Interleukin-3; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1