Abstract
Decades of lack of progress in treating many fatal malignancies of the blood-forming system is commanding interest in new approaches. Targeting early events in the leukemogenic process has long been recognized as likely to offer the information required for these diseases. Analysis of the representation of different mutations in the leukemic cells from individual patients offers a retrospective method to infer their sequence of acquisition and associated subclonal dynamics. An alternative, prospective approach is to exploit strategies for recreating human leukemia de novo using defined genetic methods. This concept is not new, but has been historically difficult to realize. A brief review of our experience in generating insights into the properties and regulation of primitive normal human hematopoietic cells serves as a reminder of how this has enabled our recent advances in developing this approach using both primary sources of chronic myeloid leukemic cells and normal cord blood cells as targets.