It is proposed to study the effects of dysregulated CF production (GM-CSF, G-CSF, Multi-CSF) alone and in combination with expression of the oncogenes myc, raf/myc and bcr/abl on murine myeloid leukemia development. The objective is to develop murine models for human myeloid leukemia development by reproducing the suspected autocrine production of CSF in some human leukemias, the known translocations involving oncogenes, particularly bcr/abl and the CSF dependence for proliferation. For this purpose a mouse line having a CM-CSF transgene and recombinant retroviruses containing the CSF genes and oncogenes will be used. Multipotential stem cells and committed progenitor cells will be infected with MPZen(GM-CSF), MPZen(Multi-CSF) or MPZen(G-CSF) and transplanted into lethally-irradiated recipients or cultured in semisolid medium. The in vivo studies will attempt to determine whether autocrine and/or elevated levels of CSF production alter multipotential cell (CFU-S) proliferation and/or commitment. These parameters will be analyzed by studying individual spleen colonies for cellular morphology and CFU-S content, ability of infected multipotential cells to compete in competitive repopulation assays and by viral integration patterns. The in vitro studies will be performed to determine whether autocrine production compared to exogenous addition of purified CSF's alters committed progenitor cell proliferation and/or differentiation. In all cases, animals and in vitro cultures will be monitored to determine whether dysregulated CSF production predisposes cells to leukemic transformation. Complementation studies will also be performed by infecting transgenic GM-CSf bone marrow cells with retroviral vectors containing myc, raf/myc or bcr/abl. In addition, normal bone marrow cells will be infected with the CSF or oncogene retroviruses in various combinations and sequences. These studies aim to determine whether autocrine CSF production in combination with oncogene expression increase myeloid leukemic transformation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA025972-11
Application #
3167125
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1983-06-01
Project End
1992-11-30
Budget Start
1991-01-04
Budget End
1991-11-30
Support Year
11
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Walter and Eliza Hall Institute Medical Research
Department
Type
DUNS #
City
Victoria
State
Country
Australia
Zip Code
VIC, -3052
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Li, C L; Johnson, G R (1995) Murine hematopoietic stem and progenitor cells: I. Enrichment and biologic characterization. Blood 85:1472-9
McArthur, G A; Longmore, G D; Klingler, K et al. (1995) Lineage-restricted recruitment of immature hematopoietic progenitor cells in response to Epo after normal hematopoietic cell transfection with EpoR. Exp Hematol 23:645-54
Li, C L; Wu, L; Antica, M et al. (1995) Purified murine long-term in vivo hematopoietic repopulating cells are not prothymocytes. Exp Hematol 23:21-5
Li, C L; Johnson, G R (1994) Stem cell factor enhances the survival but not the self-renewal of murine hematopoietic long-term repopulating cells. Blood 84:408-14
McArthur, G A; Rohrschneider, L R; Johnson, G R (1994) Induced expression of c-fms in normal hematopoietic cells shows evidence for both conservation and lineage restriction of signal transduction in response to macrophage colony-stimulating factor. Blood 83:972-81
Duhrsen, U; Novotny, J; Boyd, A W (1994) Self-renewal of a transplantable murine leukemia induced by co-culture with human stromal cell lines. Leukemia 8:490-7
Li, C L; Johnson, G R (1992) Long-term hemopoietic repopulation by Thy-1lo, Lin-, Ly6A/E+ cells. Exp Hematol 20:1309-15
Metcalf, D; Nicola, N A; Gough, N M et al. (1992) Synergistic suppression: anomalous inhibition of the proliferation of factor-dependent hemopoietic cells by combination of two colony-stimulating factors. Proc Natl Acad Sci U S A 89:2819-23
Metcalf, D (1992) Mechanisms responsible for size differences between hemopoietic colonies: an analysis using a CSF-dependent hemopoietic cell line. Int J Cell Cloning 10:116-25

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