Modification of the proliferative and differentiation capacity of stem cells following treatment with chemical and viral leukemogens.

Following treatment with a leukemogen, a variable length of time, from weeks to years, elapses before the onset of clinically apparent leukemia. The events occurring during this time are still a mystery, but as one approach to this problem we have been investigating the mechanism(s) whereby leukemogens modify the behaviour of the haemopoietic stem cells and the consequences of such alterations in terms of the proliferation and differentiation potential of such treated populations. Since the stem cells are probable "targets" for many leukemogens, our understanding of leukemogenesis, in many respects, lies in the answer we can give such questions. These studies have been greatly facilitated by the development, in the last few years, of suitable systems whereby the pluripotent haemopoietic stem cell (CFU-S) can be maintained in vitro for several months (Dexter and Testa, 1976; Dexter et al., 1977) and where the progeny of such stem cells can be induced to undergo proliferation in soft-gel media to form the variety of haemopoietic elements the lymphocytes, granulocytes, megakaryocytes and erythroid cells (Metcalf et al., 1975 b; Sredni et al., 1976; Bradley and Metcalf, 1966; Pluznik and Sachs, 1966; Metcalf et al., 1975a; Stephenson et al.. 1971). The development of these systems, and the demonstration that under appropriate conditions haemopoietic cells can be readily transformed in vitro (Rosenberg et al., 1975; Rosenberg and Baltimore, 1976; Dexter and Lajtha, 1976; Dexter, Scott and Teich, 1977) provide valuable tools in elucidating both normal and abnormal haemopoiesis. In this respect we show the effects of several chemical and viral leukemogenic agents upon haemopoietic stem cell proliferation and differentiation in bone marrow cultures and demonstrate that such treatments can induce a variety of abnormal haemopoietic conditions in vitro.