Integrated Model for the Origin of Driver and Passenger Mutations During AML Evolution. Hematopoietic stem/progenitor cells (HSPCs, shown in green) accumulate random, benign background mutations as a function of age. “X” represents these background mutations in the HSPCs and may range from ~100 to 1,000 events, depending on age. The initiating mutations are different for M1 AML cases and M3 AML cases. Because the initiating event provides an advantage for the affected cell, clonal expansion ensues, so that all of the preexisting mutations in that cell are “captured” by cloning. Each cooperating mutation gives the expanding clone an additional advantage; our data suggest that one to five events contribute to progression in most cases of AML. Each cooperating mutation is expected to capture all mutations that occurred between the initiating event and the progression event (designated as “Y” in the yellow cell). Although this number is unknown, the analysis of clonal progression of secondary AML suggests that each cooperating mutation may capture dozens to hundreds of mutations. The “founding” AML clone is designated in red. Subclones arise from the founding AML clone by acquiring a small number of additional mutations that confer an advantage to that cell, along with any additional background mutations that may have occurred in the interim (represented as “Z”).Welch JS et al. Cell. 2012;150:264-278. Reprinted with permission of Elsevier.