The molecular pathogenesis of treatment-induced (secondary) leukemias: Foundations for treatment and prevention

Acute myeloid leukemia (AML) developing after exposure to genotoxic agents has been recognized as a distinctive entity for more than 40 years. Secondary, or therapy-related, AML accounts for 10% to 20% of all AML cases. The basic and clinical investigation of these complex malignancies can be approached from four major vantage points: (1) dissection of the molecular structure of the induced genetic lesions and identification of the functional consequences of these changes, thereby providing clues to the pathogenesis of secondary AML and potentially serving as a basis for innovative therapeutic interventions; (2) identification and characterization of mechanisms of DNA damage and the orderly repair of such damage; (3) identification and application of accurate biomarkers of leukemogenesis for the purpose of risk prediction and quantification, potentially allowing recognition of patients especially susceptible to the leukemogenic effects of chemotherapy (for genetic or acquired reasons) and allowing their treatment for cancer to be modified based on this susceptibility; and (4) design and implementation of longitudinal clinical and genetic monitoring of high-risk populations (ie, individuals undergoing cytotoxic therapies for primary malignancies). In this article, we build on these themes, and attempt to integrate these seemingly disparate areas of research so that they can be more effectively used together to address the problem of secondary AML. Ultimately, the evaluation of these areas will inform our understanding of de novo leukemia and serve as a springboard for the development of new concepts of therapy and prevention.