Flt3 mutations and leukaemia

It is now 20 years since a molecular classification of acute myeloid leukaemia (AML) was initiated through the recognition 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 Organization (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 standard, 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 promyelocytic 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 patients, 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). Although 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 addition, 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 haemopoietic cells. Many years of searching have now started to bear fruit with the demonstration that acquired mutations 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.