Mechanism of T-cell lymphomagenesis: transformation of growth-factor-dependent T-lymphoblastoma cells to growth-factor-independent T-lymphoma cells.

Abstract

In a previous paper we described the induction by x-irradiation or radiation-induced leukemia virus-inoculation of two classes of lymphoid T-cell neoplasms: The first class, designated T-cell lymphoblastoma (TCLB), consists of growth-factor-dependent eudiploid cells that home to the spleen and give rise to splenic tumors on injection into syngeneic mice; the second class, designated T-cell lymphoma (TCL), consists of growth-factor-independent aneuploid or pseudodiploid cells that give rise to local tumors at the site of subcutaneous injection. This paper describes the generation of a family of growth-factor-independent aneuploid or pseudodiploid TCL cells after the injection into the thymus of growthfactor-dependent diploid TCLI cells. In contrast to the donor TCLB cells, the resulting TCL cells could be cloned in semisolid medium, produced local tumors at the site of subcutaneous injection, and proliferated in a growth-factor-independent fashion in vitro. The induced growth-factor-independent TCL cells were chromosomally and phenotypically unstable and continued to evolve both in vivo and in vitro. After propagation in the thymus, the cells often showed stable translocations in addition to the evolving aneuploidy. We propose that the chromosome abnormalities induced during the proliferation of growth-factor-dependent TCLB cells in the thymus constitute a general mechanism by which neoplastic cells progress from growth-factor dependency to independency.The mechanism of evolution of T-cell lymphomas (TCL) within the thymus of systemically irradiated or radiation-induced leukemia virus (RadLV)-inoculated C57BL/6 (B6) mice is as yet unknown. Some models suggest that in the preneoplastic thymus there exists a continuing regenerative hyperplasia of cells leading to neoplasia, with the subsequent crowding out of the normal lymphocytes by neoplastic lymphoblasts (1). This We have propagated and cloned in culture a class of T lymphoblasts from the spleens and lymph nodes of irradiated or RadLV-inoculated mice long before these had developed a thymic lymphoma (8). These neoplastic cells (T-cell lymphoblastoma; TCLB) precede the appearance of thymic lymphomas by 6-10 weeks. The isolation of these TCLB cells (8) suggests that they, or cells possessing similar properties, may be precursors to a class of autonomous neoplastic TCL cells. TCLB cells are distinct from thymic TCL cells in the following ways: (i) They are growth-factor dependent, autostimulating [producing their own growth factor(s)], and eudiploid; and (ii) they do not form colonies in soft agar unless the cultures are supplemented with exogenous conditioned medium. When injected in vivo, TCLB cells give rise to splenic tumors. Their tumorigenicity depends on the fact that they home to the spleen; they do not induce tumors at the site of subcutaneous inoculation. These characteristics of TCLB cells have been stable through prolonged propagation in vitro in mass culture, through cycles of single-cell cloning, and through repeated in vivo (splenic) passa...

Autocrine growth and progression of murine X-ray-induced T cell lymphomas.

“…In addition, though all our PXTL cells were grown from thymic lymphomas arising in vivo in irradiated mice, the cells were poorly if at all, tumorigenic when injected at doses of <5 x 105 s.c. into syngeneic mice ( Figure 5). The key to the successful establishment of factor-dependent T lymphoma lines from each in vivo thymoma was their plating at very high cell concentrations of > 107 cells/ml in DMEM-L as described previously (Haas et al, 1986). Our results extend therefore the results described by Hays et al (1985) for virus-induced thymomas in AKR mice to X-ray-induced T cell lymphomas.…”

“…We explant our thymic lymphomas as early as we can detect them in the mice, and grow them in symbiotic culture with their own fibroblastoid/epithelial monolayer as feeder (Haas et al, 1986). We explant our thymic lymphomas as early as we can detect them in the mice, and grow them in symbiotic culture with their own fibroblastoid/epithelial monolayer as feeder (Haas et al, 1986).…”

“…Assay of other growth factors IL-2 activity was assayed on the CTLL-2 cell line as described (Haas et al, 1986). Proliferation of PXTL cells is strongly dependent on cell concentration: proliferation stops at cell concentrations <4 x 104/ml.…”