Relationship between clonality and transformation in acute leukemia

In some cases of acute leukemia an initial potentially leukemogenic genetic alteration can result in clonally derived end-cells normal in appearance and numbers. We refer to this clonal expansion as preleukemia. Subsequent alterations, intrinsic or extrinsic, often referred to as transformation, result in abnormal differentiation and/or growth regulation; we refer to this as leukemia. Several issues are unresolved. Where in the hierarchy of hematopoiesis clonal expansion and transformation occur is unknown. It is quite likely that clonal expansion occurs in cells with considerable self-renewal potential--probably stem or progenitor cells. The precise site may vary in different cases and account for the diverse phenotypes of acute leukemia. How the preleukemia clone comes to dominate hematopoiesis and the fate of the residual normal stem cells and their progeny are also unknown. Likewise, there is controversy whether different models of leukemogenesis operate in different subjects. For example, are older persons or those with occupational exposure to potentially leukomogenic agents more likely to exhibit one pattern of leukomogenesis? Finally, it is unknown whether these diverse models of leukemogenesis respond differently to therapy.