Tumor necrosis factor mediates autocrine growth inhibition in a chronic leukemia.
Autocrine production of growth factors may contribute to the rapid and fatal proliferation of acute hematologic malignancies. We have investigated whether the more controlled growth of less aggressive malignancies such as chronic myeloid leukemia (CML) may be associated with autocrine production of growth inhibitory factors. TNF inhibits the growth of both normal and leukemic hemopoietic progenitor cells. We find that exogenous TNF reduces the viability and DNA synthesis of purified myeloid cells from patients with CML and inhibits myeloid colony formation by patient progenitor cells. However, unlike progenitor cells from normal donors, patient myeloid progenitor cells also constitutively express mRNA for TNF and secrete functional TNF protein in culture. This endogenous TNF impedes the growth of CML cells because anti-TNF mAb shown to neutralize bioactive human TNF increases CML cell DNA synthesis whereas non-neutralizing anti-TNF mAb has no effect. Production of TNF by CML cells is not associated with production of lymphotoxin (TNF-beta), IL-1 or IL-6. TNF-mediated autocrine growth inhibition may contribute to the maintenance of the stable, chronic phase of this disease and similar mechanisms may operate in other malignancies to limit tumor proliferation. Competition between autocrine growth promoting and inhibiting factors may underlie the observed differences in biologic behavior between acute and chronic malignancies.
Duncombe
A S
AS
Department of Haematology, Royal Free Hospital, London, U.K.
Heslop
H E
HE
Turner
M
M
Meager
A
A
Priest
R
R
Exley
T
T
Brenner
M K
MK
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D006131:Growth Inhibitors / Q000032:analysis / Q000276:immunology / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000032:analysis / Q000276:immunology / Q000473:pathology; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D007963:Leukocytes, Mononuclear / Q000032:analysis / Q000276:immunology / Q000473:pathology; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000276:immunology / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay
D000911:Antibodies, Monoclonal; D006131:Growth Inhibitors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D004247:DNA