Acute myeloid leukemia (AML) is frequently caused by genetic alterations that affect transcription factors, such as AML1-ETO and mutations affecting genes involved in signal transduction pathways, such as FLT3.
Mutations in AML1-ETO and FLT3 are two of the most common genetic alterations seen in patients with AML, but neither mutation alone can cause leukemia in animal models. Thus, it seemed the collaboration of both mutations together were necessary for blood progenitor cells to become malignant.
In a study appearing online on July 14 in advance of print publication of the August 1 issue of the Journal of Clinical Investigation, Christian Buske and colleagues from Ludwig Maximillians University report that AML1-ETO cooperates with FLT3 to potently trigger rapid and aggressive acute leukemia in mice.
This data directly support a pathogenetic model of acute leukemia, which stipulates that an activating mutation in a signal transduction pathway and a mutation in a transcription factor are required for leukemogenesis. This insight into the collaboration of two complementary classes of oncogenes in AML has direct implications for therapeutic interventions as it forms the rationale to test signal transduction inhibitors in leukemias characterized by activating mutations of receptor tyrosine kinases.