GROWTH-INHIBITORY EFFECTS OF TRANSFORMING GROWTH-FACTOR-BETA-1 MYELOID-LEUKEMIA CELL-LINES

Transforming growth factor-beta 1 is a pleiotropic cytokine involved i n a variety of biological processes in both transformed and normal cel ls, including regulation of cellular proliferation and differentiation ; its predominant action on hematopoietic cells is to inhibit cell gro wth. We used growth factor-dependent cell lines to assess TGF-beta 1 e ffects on human myeloid leukemia cell growth. While four lines were co mpletely or predominantly resistant, TGF-beta 1 inhibited effectively, albeit to various extents, the growth of 12 other cell lines. This ef fect was dose dependent and specific, because a neutralizing anti-TGF- beta 1 antibody prevented TGF-beta 1-induced growth suppression. In th e present system: basic fibroblast growth factor, known as an antagoni st of TGF-beta 1 counteracting its inhibitory effects, did not abrogat e the suppressive effects of TGF-beta 1. Other growth-stimulatory cyto kines negated the TGF-beta 1-induced inhibition in several cell lines, again to various extents. When proliferation was enhanced by growth-p romoting cytokines (e.g. granulocyte-macrophage colony-stimulating fac tor, GM-CSF, stem cell factor, SCF, or PIXY-321), some previously TGF- beta 1-sensitive cell lines acquired cellular resistance toward TGF-be ta 1-mediated growth suppression, whereas four other cell lines remain ed susceptible to TGF-beta 1 growth inhibition despite possible counte raction by other cytokines. Thus, three growth response patterns to TG F-beta 1 were seen: (1) constitutive resistance; (2) factor-dependent relative resistance; and (3) sensitivity to growth inhibition indiffer ent to counteracting cytokines. In the latter case, TGF-beta 1 did not downregulate expression of one specific growth factor receptor. These studies indicate that human myeloid leukemia cells, represented here by leukemia cell lines as model systems, exhibit heterogeneous growth responses to TGF-beta 1; its inhibitory effects can be modulated or co mpletely alleviated by positive antagonistic cytokines. The availabili ty of TGF-beta 1-susceptible and -refractory cell lines allows for det ailed investigations on the mechanisms of these regulatory pathways, t he nature of TGF-beta 1-resistance, and the possible contribution of a cquired TGF-beta 1-resistance to disease progression. (C) 1998 Elsevie r Science Ltd. All rights reserved.