Predispositions to Leukemia in Down Syndrome and Other Hereditary Disorders

Leukemia is the most common pediatric cancer and accounts for approximately one third of childhood malignancies. There are germline genetic alterations that significantly increase the risk of developing hematopoietic malignancies in childhood. In this review, we describe a number of these hereditary disorders and their clinical features. These predispositions to cancer syndromes can be attributed to DNA repair/genetic instability, RAS pathway dysfunction, bone marrow failure, telomeropathies, immunodeficiencies, transcription factor abnormalities, pure familial leukemia, and aneuploidy. We focus especially on acute myeloid leukemia associated with Down syndrome, but also include other hereditary syndromes in this review. Recent advances in high-throughput genotyping technology have identified new genetic variations prone to human leukemia. Understanding of the mechanism of leukemia development in these hereditary syndromes allows us to gain insight into leukemogenesis in general and suggests therapeutic strategies based on these findings.