Hundreds of mutations exist in leukemia cells at the time of diagnosis, but nearly all occur randomly as a part of normal aging and are not related to cancer.
Most mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability and drive clonal evolution. However, for acute myeloid leukemia (AML), normal karyotypes are common, and genomic instability is unusual. To better understand clonal evolution in AML, we sequenced the genomes of M3-AML samples with a known initiating event (PML-RARA) versus the genomes of normal karyotype M1-AML samples and the exomes of hematopoietic stem/progenitor cells (HSPCs) from healthy people. Collectively, the data suggest that most of the mutations found in AML genomes are actually random events that occurred in HSPCs before they acquired the initiating mutation; the mutational history of that cell is "captured" as the clone expands. In many cases, only one or two additional, cooperating mutations are needed to generate the malignant founding clone. Cells from the founding clone can acquire additional cooperating mutations, yielding subclones that can contribute to disease progression and/or relapse.
Timothy Ley, M.D., Chris Miller, Ph.D., David Larson, Ph.D., Robert Fulton, Mike McLellan, Aaron P Graubert, Heather Schmidt, Joelle Veizer, Michelle O'Laughlin, Joshua McMichael, Lucinda Fulton, Ryan Demeter, Tammi Vickery, Jasreet Hundal, Lisa Cook, Gary Swift, Jerry Reed, Todd Wylie, Jason Walker, Li Ding, Ph.D., Elaine R. Mardis, Ph.D., Richard K. Wilson, Ph.D.