Discovery of Gene Translocations in Childhood Acute Myeloid Leukemia

Pat Buffler and Martyn Smith
UC Berkeley
R01ES09137 and P42ES04705

Background: The cause and progression of childhood leukemia is of great interest to patients and their families and physicians as well as basic and epidemiologic researchers. Understanding how the disease starts and proceeds has implications on how it can be prevented and/or treated. Recent studies have shown that the genetic changes necessary to allow the development of the disease occur in utero. Leukemia may not develop for several years suggesting additional molecular events that are necessary for disease development. Childhood acute myeloid leukemia (AML) comprises about 20% of all childhood leukemia and represents a group of diseases with a variety of molecular subtypes. After a peak incidence of leukemias in infants with translocation of the MLL gene, children with AML exhibit the same range of abnormalities as adults, the most frequent of which is a fusion of the AML1 and ETO genes.

Advance: Unlike the age associated peak in leukemia incidence seen with the MLL translocation, the AML1-ETO fusion increases slowly during childhood and is constant throughout life. Similar leukemias sometimes develop after chemotherapy for other cancers adding additional evidence that further triggers are necessary for leukemia development. These researchers analyzed genomic sequences for 5 AML patients. Two of the patients were older than 10 years at the time of diagnosis indicative of a protracted postnatal latency period. Further studies showed that the genomic fusion sequences persist during remission.

Implication: These studies indicate that the genetic alterations leading to AML in children occur in utero, possibly as an initiating event that requires secondary genetic alterations to cause leukemia. This raises the question of whether translocation positive-preleukemic stem cells formed in utero may persist into adulthood providing a lifetime supply of cells that may progress to AML given the correct secondary genetic alteration.

Citation: Wiemels JL, Xiao Z, Buffler PA, Maia AT, Ma X, Dicks BM, Smith MT, Zhang L, Feusner J, Wiencke J, Pritchard-Jones K, Kempski H, Greaves M. In utero origin of t(8;21) AML1-ETO translocations in childhood acute myeloid leukemia. Blood. 2002 May 15;99(10):3801-5.