Differentiation in human myeloblastic leukemia studied in cell culture

Normal adult hemopoiesis orginates in pluripotent stem cells; among the early differentiated descendents of such cells are progenitors committed to the erythropoietic, granulopoietic, or megakaryocytic pathways of myeloid differentiation. These may be detected in cell culture by developmental techniques, in which progenitors form colonies in viscid or semisolid media in response to appropriate stimulation. Certain diseases of hemopoiesis also originate in pluripotent stem cells; these include chronic myeloblastic leukemia, acute myeloblastic leukemia, polycythemia vera, and idiopathic myelofibrosis-the clonal hemopathies. The hypothesis is advanced that the distribution of cell classes among patients with clonal hemopathies is determined both by the differentiation potential of each pluripotent stem cell maintaining an abnormal clone and by random events occurring during clonal expansion. The latter process may account for the large variations observed between patients when committed progenitors are assayed in cultures of marrow from patients with acute myeloblastic leukemia (AML). This variation may also be used to estimate lineage relationships in the clonal hemopathies. When applied to myelopoiesis in AML, obvious differences from the normal are not detected. The analysis is consistent with the view that the blast cell population in AML is distinct from the leukemic myelopoiesis occurring within an abnormal clone. A new assay procedure is described for progenitor cells related to blast cell proliferation. Finally, these concepts are used to develop a model for the pathogenesis and cellular characteristics of AML.