Emerging Flt3 kinase inhibitors in the treatment of leukaemia

Abstract

Acute myeloid leukaemia (AML) is characterised by the infiltration of the bone marrow with highly proliferative leukaemic cells that stop to differentiate at different stages of myeloid development and carry survival advantages. Conventionally, AML is treated with aggressive cytotoxic therapy, in eligible patients followed by allogeneic bone marrow transplantation. However, despite this aggressive treatment, many patients relapse and eventually die from the disease. Activating mutations in the coding sequence of the receptor tyrosine kinase Flt3 are found in leukaemic blasts from ~ 30% of AML patients. The mutations have been described to severely alter the signalling properties of this receptor and to have transforming activity in cell-line models and in primary mouse bone marrow. The prognosis of patients harbouring the most common Flt3 mutations tends to be worse than that of comparable patients without the mutations. Thus, Flt3 seems a promising target for therapeutic intervention. Several small molecules that inhibit Flt3 kinase activity are being evaluated for the treatment of AML in clinical trials. This review article discusses the signal transduction and biological function of Flt3 and its mutations in normal and malignant haematopoiesis and recent progress in drug development aiming at the inhibition of Flt3 kinases.

Keywords::

• acute myeloid leukaemia
• AML
• Flt3
• mutations
• signal transduction
• tyrosine kinase inhibitors

Acknowledgement

This work is supported by grants from the Deutsche Forschungsgemeinschaft (SFB293, Se 600/3-1), the José-Carreras Leukemia Foundation (R03/19f), the Interdisciplinary Centre of Clinical Research Münster (IZKF Project No. Ser2/041/04; Mül 2/096/04) and the Innovative Medizinische Forschung (IMF Project No. Ti 110506) at the University of Münster.