The specific induction of myc protooncogene expression in normal human B cells is not a sufficient event for acquisition of competence to proliferate.

Abstract

Resting human B cells can be activated to proliferate in the presence of both polyclonal antibodies to immunoglobulin pA heavy chains and B-cell growth factor (BCGF). This process appears to be temporally controlled in that the initial activation of the B cells and their responsiveness to BCGF'is carried out by polyclonal anti-p-chain antibodies alone. We have used this system to investigate the role of the c-myc gene in the cell cycle of normal human peripheral blood B cells. Our results show that the polyconal anti-pt-chain antibody-induced B-cell activation is accompanied by a specific induction of c-myc gene expression without promoting subsequent entry into the S phase unless BCGF is added. Monoclonal antibodies to either pu chain or the pan-B-cell antigen Bp35 also revealed a similar Go-to-G1 transition and activation of c-myc gene expression. However, unlike activation with polyclonal anti-p-chain antibodies, cells stimulated with these monoclonal antibodies do not acquire responsiveness to BCGF. The results imply that additional inducible functions must be present to potentiate the myc-specific function in order for the B cells to acquire the capacity to proliferate in response to BCGF. These findings are discussed in relation to the origin of B-cell malignancies.

Induction of the c-myc protooncogene after antigen binding to hapten-specific B cells.

“…These results confirmed the predictions made through the use of polyclonal stimulants by showing that such changes in c-myc mRNA levels occurred during a physiologic activation of B cells located in the Go stage of the cell cycle. Since the TD antigenic stimulation of such resting populations of B cells does not result in the progression of the cells into the G, stage of the cell cycle (5, 6), these findings strengthen observations reported in other systems that indicated that enhanced c-myc mRNA levels occurred while the activated cells were still located in Go (18)(19)(20) and may be causally related to the movement of such stimulated cells into the Go * stage of the cell cycle (21).…”

“…In the case of the TD antigenic stimulation of B cells, this stimulus will be delivered through the direct interaction between Th cells and the antigen-binding B cells (6,14,26) and will result in the commitment of the B cell to DNA synthesis. Experimental observations from both the plateletderived growth factor stimulation of 3T3 fibroblasts (16,17,20) and anti-A, stimulation of human B cells (18) support this proposed model. These published observations indicated that stimulation of enhanced levels of c-myc mRNA does not commit the cell to DNA synthesis and that such a commitment requires delivery to the activated cells of an additional stimulus.…”

“…These published observations indicated that stimulation of enhanced levels of c-myc mRNA does not commit the cell to DNA synthesis and that such a commitment requires delivery to the activated cells of an additional stimulus. Importantly, this additional stimulus, which in the case of the anti-p,-stimulated B cells consisted of T cell-derived soluble mediators, did not modulate c-myc mRNA levels (16)(17)(18).…”

Increased proto‐oncogene expression in peripheral blood T lymphocytes from patients with systemic sclerosis

“…Antiimmunoglobulin (anti-p) and B cell growth factor (BCGF) stimulation of purified human B cells studied by in situ hybridization (32) also induces a significant increase (10-20-fold) of c-myc expression in about 90% of cells within 2 hours. After 24 hours of culture, the overall expression of c-myc begins to decrease, with anti-p acting in the early G I phase and BCGF in the late GI phase (33). In contrast, Ki-rus and Ha-rus do not show detectable differences in hybridization between resting and stimulated B cells (32).…”

Identification of murine CBFα1, a runt domain transcription factor, as a putative Myc collaborator in T cell lymphoma

“…The rate-limiting steps in Myc transformation are not fully understood but may be explained by the fact that Myc alone does not immortalise haemopoietic cells 3 or that additional changes are required to overcome cell cycle checkpoint controls. 4 Also, overexpression of Myc in serum-starved fibroblasts induces apoptosis rather than proliferation, suggesting that this propensity may have to be countered for efficient tumorigenesis in vivo. 5 Genes that could play a role in completing malignant transformation by Myc have been identified by generation of doubly transgenic mice which succumb more rapidly than either parental type.…”