title: Central role of tumour necrosis factor, GM-CSF, and interleukin 1 in the pathogenesis of juvenile chronic myelogenous leukaemia.
abstract: In previous studies on patients with juvenile chronic myelogenous leukaemia (JCML), we found excessive proliferation of malignant monocyte-macrophage elements in the absence of exogenous growth factor, and impaired growth of normal haematopoietic progenitors. In the current study, six newly-diagnosed JCML patients were investigated to characterize the disease further. In co-cultures, JCML cell culture supernatant as well as patient plasma obtained at diagnosis produced a striking reduction in numbers of control marrow BFU-E, CFU-GM, CFU-Meg and CFU-GEMM colonies. Monoclonal anti-tumour necrosis factor alpha neutralizing antibodies (anti-TNF-alpha Ab) abolished these inhibitory properties. In sharp contrast, JCML supernatants exerted a marked growth-promoting effect on autologous JCML cells cultured in clonogenic assays. Anti-TNF-alpha Ab and anti-granulocyte-macrophage colony-stimulating factor neutralizing antibodies (anti-GM-CSF Ab) both reversed the stimulating effect. Recombinant GM-CSF and recombinant TNF alpha produced a profound increase in JCML colonies when tested individually and anti-GM-CSF Ab reversed the TNF-alpha effect. Expression studies of TNF-alpha and TNF-alpha receptor genes of cultured JCML cells demonstrated mRNAs for both. Further, TNF-alpha activity was assayed in a wide variety of cell culture supernatants and in normal and patients' plasma, and only the JCML specimens showed increased TNF-alpha values. Recombinant interleukin-1 alpha (IL-1 alpha) also stimulated JCML colony growth, but polyclonal anti-IL-1 neutralizing antibodies did not suppress JCML colony numbers nor did it reverse the effects of TNF-alpha or GM-CSF. The evidence indicated that the JCML monokine which inhibits normal haematopoiesis is TNF-alpha and that the endogenously-produced TNF-alpha and GM-CSF from JCML cells play an important role in the pathogenesis of the disease by acting as autocrine growth factors. IL-1 alpha also stimulates JCML cell proliferation as an accessory factor and augments the effect of GM-CSF, TNF-alpha or both.
authors.affiliation: Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: M H
authors.initials: MH
authors.lastname: Freedman
authors.forename: A
authors.initials: A
authors.lastname: Cohen
authors.forename: T
authors.initials: T
authors.lastname: Grunberger
authors.forename: N
authors.initials: N
authors.lastname: Bunin
authors.forename: R E
authors.initials: RE
authors.lastname: Luddy
authors.forename: E F
authors.initials: EF
authors.lastname: Saunders
authors.forename: N
authors.initials: N
authors.lastname: Shahidi
authors.forename: A
authors.initials: A
authors.lastname: Lau
authors.forename: Z
authors.initials: Z
authors.lastname: Estrov
mesh_terms: D001483:Base Sequence; D001853:Bone Marrow / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D003114:Colony-Forming Units Assay; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D006410:Hematopoiesis / Q000276:immunology; D006801:Humans; D007223:Infant; D007375:Interleukin-1 / Q000276:immunology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000276:immunology*; D008297:Male; D008969:Molecular Sequence Data; D011956:Receptors, Cell Surface / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins / Q000276:immunology; D014407:Tumor Cells, Cultured / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D007375:Interleukin-1; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor