Review FLT3 MUTATIONS AND LEUKAEMIA It is now 20 years since a molecular classification of acute myeloid leukaemia (AML) was initiated through the recog- nition of a number of leukaemia-specific cytogenetic abnormalities and their role as independent prognostic factors (Bloomfield et al, 1984). The intensive study of some of these markers, in particular the fusion transcripts from chromosomal translocations, has provided considerable insight into the underlying disease pathogenesis through characterization of the resulting aberrant gene products and their biological and clinical consequences. This has now been incorporated into the recent World Health Organiza- tion (WHO) classification of haemopoietic and lymphoid neoplasms in which AML patients with four well-defined recurring cytogenetic abnormalities have been put together as a subgroup (Harris et al, 1999). In general, however, patients are divided into three different risk groups based on cytogenetics: those with favourable, intermediate or stand- ard, and poor risk disease. In some centres, the response to initial therapy is also taken into account (Wheatley et al, 1999). This classification has paved the way for a move from the indiscriminate use of high-dose chemotherapy for all patients to a more risk-adapted treatment approach. Patients with favourable cytogenetics, i.e. t(15;17), t(8;21) and inv(16), have particularly benefited from an improved understanding of the molecular pathology of their disease through identification of potential therapeutic targets. For example, the addition of all-trans retinoic acid (ATRA) during induction chemotherapy for acute prom- yelocytic leukaemia (APL) patients with the PML ⁄ RARa (promyelocytic leukaemia ⁄ retinoic acid receptor alpha) fusion gene has increased the 5-year survival a further 20–30% compared with chemotherapy alone (Tallman et al, 1997; Burnett et al, 1999). Patients with poor risk disease have adverse survival, which hardly exceeds 20% at 5 years (Grimwade et al, 1998). They often have complete or partial loss of genetic material, e.g. )7, )5, del(5q), del(3q) or complex karyotypes, abnormalities that are currently less suitable candidates for targeted therapy. Approximately two-thirds of newly diagnosed AML pa- tients, however, have intermediate ⁄ standard risk disease; their remission rate is similar to that of patients with favourable disease, but their outcome is hampered by an increased relapse rate (Grimwade et al, 1998). Alth- ough some of these patients have identifiable cytogenetic abnormalities that may allow the development of novel therapies, the majority of patients,  50% of all patients, have a normal karyotype. There has therefore been much interest in identifying further molecular markers of leukaemia that could help to improve the prognostic stratification of patients. In addi- tion, with clear evidence for a multistep pathogenesis from both mouse models of leukaemia and the variable outcome for patients within defined cytogenetic groups, knowledge of co-operating mutations may further assist in improving therapy. Mutations in growth factor receptors and their downstream signalling molecules have long been obvious candidates for causing dysregulation of the delicate balance between proliferation and differentiation in hae- mopoietic cells. Many years of searching have now started to bear fruit with the demonstration that acquired muta- tions in the tyrosine kinase receptor gene, FLT3, are common in AML and have a major impact on prognosis. This review will outline the current knowledge on these mutations and their biological and clinical significance in leukaemia. FLT3 FLT3 (fms-like tyrosine kinase 3), also known as stem cell tyrosine kinase-1 (STK1) or fetal liver tyrosine kinase-2 (FLK-2), is one of the class III tyrosine kinase (TK) receptors that share sequence homology and structural characteris- tics. The latter include five immunoglobulin-like domains in the extracellular region, an intracellular juxtamembrane (JM) domain, two TK domains interrupted by a kinase insert and a C-terminal tail (Agnes et al, 1994) (Fig 1). The gene is located at chromosome 13q12 and consists of 24 exons (previously reported as 21) (Rosnet et al, 1991; Abu-Duhier et al, 2001a). FLT3 is predominantly expressed on haemopoietic pro- genitor cells in the bone marrow, thymus and lymph nodes (Rosnet et al, 1993), but is also found on other tissues such as placenta, brain, cerebellum and gonads (Maroc et al, 1993). Interaction with its ligand (FL) results in receptor dimerization, autophosphorylation and the subsequent phosphorylation of cytoplasmic substrates that are involved in signalling pathways regulating the proliferation of pluripotent stem cells, early progenitor cells and immature lymphocytes (Lyman, 1995). This interaction is influenced by other cytokines such as Kit ligand (KL). In fact, when primitive human progenitor cells are stimulated in vitro with either FL or KL alone, they show little or no proliferative response, but both ligands together synergistically enhance growth (Hannum et al, 1994). Further evidence for the Correspondence: Rosemary E. Gale, Department of Haematology, University College London, 98 Chenies Mews, London WC1E 6HX, UK. E-mail: rosemary.gale@ucl.ac.uk British Journal of Haematology, 2003, 122, 523–538 Ó 2003 Blackwell Publishing Ltd 523