New concepts in the treatment of acute myeloid malignancies: selected pathways for targeted therapy

Acute myeloid leukemia (AML) and myelodysplasia (MDS) continue to present formidable treatment challenges as there is not yet a "standard approach" that reliably and safely cures the majority of adults with these disorders. Understanding the basic cellular and molecular biology of leukemia is vital to the development of better treatment approaches. All malignant cells, including leukemias, carry survival advantages compared to their normal counterparts. These survival advantages are particularly evident when the cells face both normal environmental stressors as well as extreme stressors of potentially lethal DNA damage. The impact of such stressors is ultimately determined by the signaling pathways and resultant cellular activation, including alterations in cellular growth, differentiation, survival and death. It is our improving understanding of these signaling pathways, both normal and malignant, that provide the targets for novel therapies. In this review article, we will focus on several signaling pathways, as well as the regulation of the cell cycle, that not only represent potentially accessible sites for intervention in myeloid malignancies, but those that are actively being studied.