The development of the genetic studies on acute myeloid leukemias (AMLs) has led to the identification of some recurrent genetic abnormalities. Their discovery was of fundamental importance not only for a better understanding of the molecular pathogenesis of AMLs, but also for the identification of new therapeutic targets. In this context, it is essential to identify AML-associated “driver” mutations, which have a causative role in leukemogenesis. Evidences accumulated during the last years indicate that activating internal tandem duplication mutations in FLT3 (FLT3-ITD), detected in about 20% of AMLs, represents driver mutations and valid therapeutic targets in AMLs. Furthermore, the screening of FLT3-ITD mutations has also considerably helped to improve the identification of more accurate prognostic criteria and of the therapeutic selection of patients. 1. Introduction The FMS-like tyrosine (FLT3) gene encodes a class III receptor tyrosine kinase, sharing structural and sequence homologies with family members, including c-kit, c-FMS, FLT1, and PDGF-βR. FLT3 plays a key role in the control of hematopoiesis. High levels of WT FLT3-expression have been observed in various hematological malignancies including the majority of acute myelogenous leukemias (AMLs) and B-cell acute lymphoblastic leukemias (ALLs). In line with these findings, FLT3 is clearly expressed in the majority of leukemia cell lines and, particularly, in monocytic cell lines. In addition to these frequent abnormalities, in 1996 it was discovered that in AMLs FLT3 is frequently mutated; in fact, internal tandem duplications (ITDs) within the juxtamembrane domain of FLT3 have been reported in about 25% of patients, making it one of the most single frequent mutations in adult AMLs [1]. Subsequently, it was shown that these FLT3-ITD mutations resulted in an uncontrolled receptor activation, characterized by ligand-independent receptor dimerization, constitutive FLT3 signaling with consequent activation of STAT5 and of the RAS/MAPK and PI3？K pathways. In 2001, another frequent class of FLT3 mutations causing constitutive receptor activation occurred at the level of the activation loop of the second kinase domain [2]; this group of mutations is represented by various abnormalities, such as substitutions, small deletions, or insertions mainly occurring at codons 835 and 836 and is detected in about 5–10% of AMLs [2]. Finally, more recently, a group of point mutations within the juxtamembrane domain of FLT3 have been described in about 1% of AML patients; these mutations involve various amino
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