Conversion of factor-dependent myeloid cells to factor independence: autocrine stimulation is not coincident with tumorigenicity.

It has been postulated that the disruption of the normal hormonal regulation of blood cell formation and proliferation leads to the autonomous growth of hematopoietic progenitors or stem cells and thus to leukeamia. We have utilized established hematopoietic cell lines to establish the different mechanism by which growth autonomy is acquired. The analysis of thirteen spontaneous factor-independent mutants revealed that the majority (12/13) secreted a factor that stimulated growth of the parental cell line. Thus, autocrine stimulation may be a important mechanism by which normal growth control is disrupted. This is supported by the observation of Young and Griffin (1987) that some cells isolated from patients with acute myeloblastic leukemia (AML) autogenously produce growth factor. In the majority of Dind mutants more closely examined, growth factor gene activation was due to the juxtapostion of a retrotransposon. Although the exact nature of the involvement of human retroviruses in inducing leukemia has not been elucidated, one could envisage that altered growth factor regulation due to integration of the virus may play an important role. The existence of a second class of Dind mutants that have obtained factor-independence by a mechanism not involving factor production concurs with the acquisition of factor-independent growth in hematopoietic cells after introduction of some oncogenes. Several models have been proposed to explain how oncogenes may "short circuit" and thus activate the normal signal transduction pathway by mimicking the active receptor, transducer, or effector (Weinberg, 1985). To investigate more closely the role of autocrine stimulation in the induction of growth autonomy and tumorigenicity, retroviral vectors expressing either GM-CSF or IL3 were introduced into factor-dependent hematopoitic cell lines. Non-linear clonability of infected cell lines in the absence of exogenous growth factor and inhibition of proliferation by antiserum supported a model of autocrine stimulation. However, a secondary event, correlated with amount of factor released, often occurred that abrogated the requirement for secreted CSF. Growth of cells in which this alteration had occured was cell-density independent and could not be blocked by antibody. It has been postulated that autogenous factor may react with its receptor intracellularly (Lang et al., 1985). The results presented here cannot exclude that the secondary events may allow the internal interaction of receptor and factor.(ABSTRACT TRUNCATED AT 400 WORDS)