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 com mon theme in acute myeloid leukaemia (AML) associated with balanced recipro cal translocations is the involvement of transcription factors as one or bo th of the fusion partners. Transcription factors commonly involved in chrom osomal translocations include core binding factor (CBF), retinoic acid rece ptor alpha (RAR alpha), ETS family of transcription factors and homeobox ge ne (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 clo ned. However expression of transcription factor fusion proteins is not sufficien t to induce a leukaemic phenotype, as evidenced in part by the long latenci es required for disease development in the murine models of the disease. An emerging paradigm is the co-operation between constitutively activated tyr osine kinase molecules, such as FLT3, and transcription factor fusions in t he pathogenesis of AML. In such a model, the activated tyrosine kinase conf ers proliferation and/or anti-apoptotic activity to the hematopoietic cells , while the transcription factor fusion impairs normal differentiation path ways with limited effect on cellular proliferation.