Core-binding factor acute myeloid leukemia in pediatric patients enrolled in the AIEOP AML 2002/01 trial: screening and prognostic impact of c-KIT mutations

The proto-oncogene c-KIT, which encodes a receptor for stem cell factor (SCF), belongs to the type-III receptor of the tyrosine kinase subfamily and is characterized by five extracellular immunoglobulin-like domains, a single transmembrane helix (TM), a cytoplasmic juxtamembrane domain(JMD), and a kinase domain. Abnormal activation of c-KIT/SCF growth signal has been frequently documented to occur in cancers, including hematological malignancies, and has been frequently associated with poor prognosis in adults with acute myeloid leukemia (AML) harboring aberrancies at core-binding factor genes (CBF). c-KIT mutations have been reported in pediatric CBF-rearranged AML at frequencies ranging from 15 to 54.5%; however, their prognostic significance is still debated. Mutations of c-KIT occur in the extracellular portion of the receptor implicated in dimerization within exon 8, in the TM-JMD domain within exon 11 and in the activation loop of the tyrosine kinase domain within exon 17, this mediating the constitutive activation of the receptor.