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-α 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-α 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-α produced a profound increase in JCML colonies when tested individually and anti-GM-CSF Ab reversed the TNF-α effect. Expression studies of TNF-α and TNF-α receptor genes of cultured JCML cells demonstrated mRNAs for both. Further, TNF-α 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-α values. Recombinant interleukin-1 alpha (IL-1α) 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-α or GM-CSF. The evidence indicated that the JCML monokine which inhibits normal haematopoiesis is TNF-α and that the endogenously-produced TNF-α and GM-CSF from JCML cells play an important role in the pathogenesis of the disease by acting as autocrine growth factors. IL-1α also stimulates JCML cell proliferation as an accessory factor and augments the effect of GM-CSF, TNF-α or both.link_to_subscribed_fulltex