Flt3 in aml

FMS-like tyrosine kinase 3 (FLT3) receptor and its ligand play a significant role in human hematopoiesis and the proliferation and malignant transformation of primitive hematopoietic cells. FLT3 mutations are observed in approximately 30 % of adult AML, 1–3 % of adult B-ALL and 2–5 % of MDS patients. Binding of FLT3 ligand to FLT3 receptor results in autophosphorylation and activation of downstream pathways that promote cell proliferation including the MAPK/ERK, Pi3K/AKT, signal transducer activator of transcription (STAT5), and BCL2-associated X protein (BAX) pathways. There are two major types of FLT3 mutations: The FLT3 internal tandem duplication (ITD) results from duplication and insertion of a fragment of the juxtamembrane domain coding sequence, whereas the less common tyrosine kinase domain (TKD) results from a missense point mutation within the activation loop of the second TKD. Studies suggest that patients with FLT3-ITD have significantly elevated peripheral blood white cell counts and increased bone marrow blasts at diagnosis. Furthermore, they have a significantly higher induction death rate, increased relapse risk, inferior event-free survival, and decreased overall survival. Recent studies have further indicated that FLT3-ITD mutations may be a significant prognostic indicator in patients with AML and diploid karyotype, but not in those with core-binding factor AML or AML with unfavorable cytogenetics. Also, presence of FLT3-ITD mutation may be a negative prognostic marker, not only at diagnosis but also at first relapse. Several small-molecule FLT3 inhibitors are currently in clinical trials and may improve responses for patients with FLT3- mutated AML.