Molecular genetics of acute myeloid leukaemia

Elucidation of the molecular genetic basis of leukaemias has relied on the cloning and characterization of recurring chromosomal translocations. A common theme in acute myeloid leukaemia (AML) associated with balanced reciprocal translocations is the involvement of transcription factors as one or both of the fusion partners. Transcription factors commonly involved in chromosomal translocations include core binding factor (CBF), retinoic acid receptor alpha (RARalpha), ETS family of transcription factors and homeobox gene (HOX) family members. In addition, the recruitment of transcriptional co-activators and co-repressors by these transcription factors suggests that these proteins also may play a critical role in leukaemogenesis. In support of this hypothesis' at least three fusions associated with leukaemias and involving transcriptional co-activators CBP and p300 have been recently cloned. However expression of transcription factor fusion proteins is not sufficient to induce a leukaemic phenotype, as evidenced in part by the long latencies required for disease development in the murine models of the disease. An emerging paradigm is the co-operation between constitutively activated tyrosine kinase molecules, such as FLT3, and transcription factor fusions in the pathogenesis of AML. In such a model, the activated tyrosine kinase confers proliferation and/or anti-apoptotic activity to the hematopoietic cells, while the transcription factor fusion impairs normal differentiation pathways with limited effect on cellular proliferation.