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. 2006 Jan 31;103(5):1486-91.
doi: 10.1073/pnas.0510616103. Epub 2006 Jan 23.

Inactivation of PU.1 in adult mice leads to the development of myeloid leukemia

Donald Metcalf  1 , Aleksandar Dakic, Sandra Mifsud, Ladina Di Rago, Li Wu, Stephen Nutt
Affiliations

Inactivation of PU.1 in adult mice leads to the development of myeloid leukemia

Donald Metcalf et al. Proc Natl Acad Sci U S A. .

Abstract

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.

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Figures

Fig. 1.
Fig. 1.
Development of myeloid leukemia in PU.1-/- mice. (A) Survival of PU.1-/- and PU.1+/+ mice after the injection of poly IC. (B) Development of leukemia in PU.1-/- but not PU.1+/+ mice.
Fig. 2.
Fig. 2.
Myeloid leukemia in a PU.1-/- mouse. (A)(Left) PU.1-/- mouse with myeloid leukemia. Note enlarged liver (large arrow) and spleen (small arrow). (Right) Control PU.1+/+ mouse. (B) Three fields of cytocentrifuged bone marrow cells from a mouse with myeloid leukemia; bl, blast cells; promyel, promyelocytes; myel, myelocytes. (C) FACS analysis of bone marrow and spleen cells from a PU.1-/- mouse with myeloid leukemia compared with cells from a control PU.1+/+ mouse.
Fig. 3.
Fig. 3.
Morphology of myeloid leukemic cells and colonies grown from them. (A) Bone marrow from a PU.1-/- mouse with myeloid leukemia. (B) Spleen from the same animal as A. (C) Granulocytic colony formed by normal marrow cells after stimulation by 10 ng/ml G-CSF. (D) Granulocytic colony formed by postinduction PU.1-/- marrow cells after stimulation by 10 ng/ml G-CSF. (E) Autonomous granulocytic colony formed by unstimulated myeloid leukemic cells. Arrows indicate maturing granulocytic cells.
Fig. 4.
Fig. 4.
Colony formation in vitro by PU.1-/- leukemic cells. (A) Linearity of spontaneous colony formation by cells from three mice with myeloid leukemia. (B) Colony formation by 10,000 cells from 12 mice with myeloid leukemia. Note the variable frequency of colony-forming cells and the examples where IL-3 or GM-CSF stimulated the formation of increased numbers of colonies. All stimuli were used at a final concentration of 10 ng/ml. (C) Colony formation by recloned leukemic colony cells in cultures stimulated by 10 ng/ml IL-3. Note the progressive decline in the generation of clonogenic cells on serial passage. Each point represents data from a single colony.
Fig. 5.
Fig. 5.
Production of IL-3 or GM-CSF by myeloid leukemic cells. (A) Stimulation by leukemic cell-conditioned media (C.M) of proliferation of IL-3-dependent BaF3 cells and the neutralization of this activity by a specific anti-IL-3 monoclonal antibody. (B)(Upper) Detection of transcription of IL-3 or GM-CSF by myeloid leukemic cells using RT-PCR. (Lower) Southern analysis using EcoR1 to document monoallelic rearrangement of the IL-3 gene. wt, wild type.
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