THE SECONDARY LEUKEMIAS - CHALLENGES AND RESEARCH DIRECTIONS

Acute myelogenous leukemia (AML) arising following exposure to genotox ic agents has been recognized as a distinctive entity for more than 40 years. Secondary, or therapy-related, AML accounts for 10%-20% of all AML cases. This review addresses four overarching areas of investigat ion focused on secondary AMLs: 1) dissection of the molecular structur e of the induced genetic lesions and identification of the functional consequences of these changes, thereby providing clues to the pathogen esis of secondary AML and potentially serving as a basis for innovativ e therapeutic interventions; 2) identification and characterization of mechanisms of DNA damage and the orderly repair of such damage; 3) id entification and application of accurate biomarkers of leukemogenesis for the purpose of risk prediction and quantification, potentially all owing recognition of patients especially susceptible to the leukemogen ic effects of chemotherapy (for genetic or acquired reasons) and allow ing their treatment for cancer to be modified on the basis of this sus ceptibility; and 4) design and implementation of longitudinal clinical and genetic monitoring of high-risk populations (i.e., individuals un dergoing cytotoxic therapies for primary cancers). This review of the literature relating to these areas builds upon these themes and attemp ts to synthesize these seemingly disparate areas of research so that t hey can be more effectively utilized together to address the problem o f secondary AML. Ultimately, the evaluation of these areas will improv e our understanding of de novo leukemia and will serve as a springboar d for the development of new concepts of therapy and prevention.