Model for evolution of genetic changes in acute myeloid leukemia. Long-lived hematopoietic stem cells (HSC) acquire a number of benign mutations (1,2,3) that do not alter the function of these cells during the life of the individual. Even though most of them are irrelevant, they are all present in the individual cell when it acquires the critical mutation (4) that sets the cancer in motion. Additional mutations (5) then cause the transformed cell to progress to overt leukemia; AML in this case. Figure included with permission (Walter MJ, et al. Per Med 2009;6:653).⁹