This project aims to test the relevance for human disease in recent observations in the mouse that lead to the hypothesis that transformation of hemopoietic and related cells can result from the abnormal production of a hemopoietic growth factor by a hemopoietic progenitor cell with consequent autostimulation. Major emphasis will be given to the analysis of material from patients with acute nonlymphocytic leukemia and Hodgkin's disease, although other diseases, including myeloproliferative disorders, acute lymphocytic leukemia, and urticaria pigmentosa will also be examined. Tissue culture techniques will be used to test whether the abnormal cells are dependent for their growth on hemopoietic growth factors and whether they are themselves producing these factors. The work will focus on one particular hemopoietic growth factor, the T-cell lymphokine, P-cell stimulating factor, because of its involvement in the murine model of autostimulatory leukemogenesis and because this factor acts on the pluripotential hematopoietic stem cell and progenitor cells of multiple hematopoietic lineages. However, the tissue culture experiments planned will also take into account the possibility that autostimulation could involve other hemopoietic growth factors, which will be detected by their effects on the cell that produces them. Recombinant DNA techniques will be used to investigate whether mRNA for PSF or a related molecule is transcribed in the abnormal cells and whether the PSF gene or its contest is altered. These techniques will permit positive identification of the autostimulatory role of PSF or a related molecule in a given condition, and by analysis of freshly isolated cells establish that abnormal production of PSF is occurring in the patient in vivo and not merely in lines derived from the patient. The importance of determining whether an autostimulatory mechanism is involved in a given human disease lies in the possibility that measures that would block stimulation by the growth factor, e.g., treatment with either analogues of the growth factor that block but do not stimulate, or with monoclonal antibodies directed against the growth factor or its receptor, might interrupt the autostimulation and constitute a relatively selective and nontoxic mode of therapy. (J)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA038684-02
Application #
3176879
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1985-02-01
Project End
1986-09-30
Budget Start
1986-02-01
Budget End
1986-09-30
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Walter and Eliza Hall Institute Medical Research
Department
Type
DUNS #
City
Victoria
State
Country
Australia
Zip Code
3050
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Schrader, J W; Leslie, K B; Clark-Lewis, I et al. (1988) Growth factor-related mechanisms of leukemogenesis. Adv Exp Med Biol 241:265-71
Ziltener, H J; Clark-Lewis, I; Fazekas de St Groth, B et al. (1988) Monoclonal antipeptide antibodies recognize IL-3 and neutralize its bioactivity in vivo. J Immunol 140:1182-7
Ziltener, H J; Clark-Lewis, I; Fazekas de St Groth, B et al. (1987) Antipeptide antibodies define the NH2-terminal structure of the pan-specific hemopoietin interleukin 3. J Immunol 138:1105-8
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Schrader, J W; Ziltener, H J; Leslie, K B (1986) Structural homologies among the hemopoietins. Proc Natl Acad Sci U S A 83:2458-62
Clark-Lewis, I; Aebersold, R; Ziltener, H et al. (1986) Automated chemical synthesis of a protein growth factor for hemopoietic cells, interleukin-3. Science 231:134-9