Jason Gotlib, MD, MS
Dr. Gotlib indicated no relevant conflicts of interest.
Ding L, Ley TJ, Larson DE , et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by wholegenome sequencing. Nature. 2012. 481:506-510.
It is now widely embraced that tumor initiation and progression follows a Darwinian process of natural selection of tumor clones and sub-clones derived from somatic cell mutations.1 The phenotype and natural history of cancers are shaped by several factors including a spectrum of tumor-specific genetic and epigenetic changes that occur over time, the tissue microenvironment that may act to either promote or constrain tumor growth, and external “artificial selection” pressures, such as radio/chemotherapy. Using the language of evolutionary theory, cancers exist as part of complex ecosystems, wherein cancer sub-clones that are best adapted to their geographic niche are more likely to survive and reproduce.2 Selective pressures may promote the expansion or extinction of specific cancer cell populations, resulting in a clonal architecture that mimics Darwin’s branching evolutionary tree of species.
Death in AML is principally related to relapse due to the emergence of clones that have escaped the body’s mechanisms to suppress cancer, developed resistance to treatment, or both. In order to better characterize the molecular basis for AML transformation, Li Ding and colleagues from Washington University, St. Louis, utilized whole-genome sequencing to profile genetic mutations in paired samples taken at the time of diagnosis and at the time of relapse. Two basic patterns of clonal evolution emerged from investigation of paired specimens from eight AML patients: in the first, relapse was related to the acquisition of new mutations in the dominant clone identified in the primary leukemia sample; in the second, a minor subclone of the founding clone at the time of diagnosis gained additional mutations and expanded at relapse. For example, in one patient, the known recurrent AML mutations DNMT3A, NPM1, PTPRT, SMC3, and FLT3 were identified in the dominant clone at diagnosis. A minor sub-clone with a distinct cluster of mutations expanded at relapse due to the acquisition of additional mutations in ETV6, MYO18B, and the fusion gene WNK1-WAC. The pattern of relapse described in the first was identified in three patients, and the remaining five patients conformed to the second pattern. Despite chemotherapy, the founding clone was observed in all eight patients at both diagnosis and relapse. In addition, analysis of relapse versus diagnosis-specific mutations revealed a statistically significant increase in transversions. Compared with transitional mutations in which one purine or pyrimidine nucleotide is substituted for another, transversional mutations involve substitution of a purine nucleotide for a pyrimidine nucleotide or vice versa, and this latter type of mutation is associated with DNA damage mediated by cytotoxic therapy.
These data that illuminate the patterns of clonal evolution and the dynamic persistence of leukemia cells in the face of conventional chemotherapy provide a new level of clarity of the biologic heterogeneity of AML and are a humbling reminder of the vexing inadequacies of current treatment. The complex genetics of relapsed AML is in stark contrast to chronic-phase CML, where BCR-ABL is the primary driver mutation and is highly susceptible to imatinib and second-generation tyrosine kinase inhibitors. In AML, the adoption of treatments that target a common “Achilles heel” is challenged by the genetic diversity of sub-clones highlighted in this study. Although elimination of leukemia stem cells has gained traction as a rational therapeutic strategy, complex sub-clonal architecture and relative quiescence of this primitive cell population may confound such efforts. Thus, multi-pronged approaches that additionally focus on the tumor microenvironment and epigenetic modulation of tumor cell gene expression will be needed to generate sufficient selection pressures on leukemia sub-clones to reduce their fitness and survival.
- Nowell PC. The clonal evolution of tumor cell populations. Science. 1976. 194:23-28.
- Greaves M and Maley CC. Clonal evolution in cancer. Nature. 2012. 481:306-313.
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