Clonal origin of leukemia: site of origin in the stem cell hierarchy and the significance of chromosomal changes.

Human leukemias and related diseases appear to be clonal in nature. In certain diseases, the initial cell involved is most likely the totipotential hematopoietic stem cell (HSC), i.e., the stem cell capable of giving rise to all hematopoietic cells, lymphoid as well as myeloid. In other diseases, an HSC of more restricted potentiality may be the primary cell producing the disease but, alternatively, all could arise from the totipotential cell. Cells in the clone are often identifiable by the presence of morphologic or chromosomal abnormalities, but in a given clone all cells may not express the abnormalities. In some but not in all patients who have been studied, residual normal HSC have been detected that are not part of the clone. Our current therapeutic attempts designed to cure at least some of these diseases are based on the concept of "total cell kill.' In order to achieve this goal, the clone of tumor cells must be eradicated. To monitor this attempt and carry out therapy in a more scientific fashion, better means of identifying all cells in the clone are needed. If the disease involves the totipotential HSC, for which we assume there is no precursor cell in postfetal life, then there must be residual, normal HSC or the disease cannot be eradicated in this manner without also eradicating the patient.