From kinases to cancer: Leakiness, loss of autoinhibition and leukemia

Abstract

The class III receptor tyrosine kinase (RTK) "Fms-like tyrosine kinase 3" (FLT3) plays a key role in early hematopoesis. In acute myeloid leukemia (AML) two classes of activating FLT3 mutations are known: internal tandem duplications (FLT3-ITD) in the juxtamembrane domain and point mutations in the tyrosine kinase domain (FLT3-TKD). Recently, a third class of activating mutations was discovered, single point mutations in the juxtamembrane domain (FLT3-JM-PM). Since the crystal structure of the inactive conformation of FLT3 has recently been resolved the role of the juxtamembrane (JM) domain, serving as a key autoinhibitory element regulating kinase activity, was elucidated. Mutations in the JM domain seem to perturb the autoinhibitory activity of the JM domain thereby inducing autonomous activation of the kinase. These findings have important clinical implications. Routine screenings for mutations in FLT3 in leukemia diagnostics should also analyze point mutations in the JM domain of FLT3 and patients harbouring FLT3-JM-PM might benefit from experimental therapeutic approaches with FLT3 inhibitors. The identification of FLT3-JM-PM is a remarkable example how single point mutations in the structurally important JM domain can turn RTKs into oncogenes. ©2006 Landes Bioscience.