Antileukemic activity of Flt3 ligand in murine leukemia.
Flt3-ligand (Flt3-L) is an early acting costimulatory cytokine that has been shown to possess antitumor properties in murine solid tumor models. Flt3-L is a trans-membrane protein (tm) but can be proteolytically cleaved to a soluble form, which is also biologically active. In this study, the antitumor effect of both soluble and tmFlt3-L was evaluated in a mouse leukemia model. To mimic the multiorgan involvement characteristic of human leukemia, a factor-dependent cell line FDC.P1 was made leukemogenic by transfection with the human BCR/ABL gene. The resulting cell line, AW, expresses BCR/ABL RNA and protein. It maintains a similar in vitro growth rate as the parent cell line, but unlike the parent cell line, AW cells are factor independent and tumorigenic. Growth of FDC.P1 and AW cells are unaffected by the addition of soluble human Flt3-L to the culture medium. Also, AW growth is unaltered after transduction with a retroviral vector expressing the tm isoform of human Flt3-L (AW/tmFlt3-L). When 10(5) AW cells were i.v. injected into syngeneic DBA/2 mice, fatal leukemia developed in nine of nine (100%) mice within 4-6 weeks with involvement of the blood, bone marrow, spleen, and thymus. Systematic administration of soluble human Flt3-L (500 microg/kg/day) for 10 days protected mice from leukemia, with 11 of 17 mice tumor free at week 8 (64.7%) The tm isoform of Flt3-L also was protective. When 10(4) AW/tmFlt3-L cells were injected i.v. into mice, only 35.7% (5 of 14) developed leukemia versus 100% in control groups. Adoptive transfer of immunity was also demonstrated; T cells obtained from tumor-free animals conferred protection to 87% (seven of eight) naive mice challenged with AW cells. These results demonstrate that both soluble and membrane-bound human Flt3-L has antitumor activity in this leukemia model.
Wang
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A
Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis 46202, USA.
Braun
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SE
Sonpavde
G
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Cornetta
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K
D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use / Q000633:toxicity*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D005260:Female; D016313:Genes, abl; D006801:Humans; D007942:Leukemia, Experimental / Q000473:pathology / Q000517:prevention & control*; D008565:Membrane Proteins / Q000235:genetics* / Q000627:therapeutic use / Q000633:toxicity*; D051379:Mice; D008811:Mice, Inbred DBA; D020033:Protein Isoforms / Q000235:genetics / Q000627:therapeutic use / Q000633:toxicity; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity; D014162:Transfection; D051941:fms-Like Tyrosine Kinase 3
D016588:Anticarcinogenic Agents; D008565:Membrane Proteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; C084881:flt3 ligand protein; C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3