Pathogenesis of acute myeloid leukaemia and inv(16)(p13;q22): a paradigm for understanding leukaemogenesis?
Acute myeloid leukaemia (AML) has been proposed to arise from the collaboration between two classes of mutation, a class I, or proliferative, mutation and a class II, or blocking, mutation. A limitation of this so-called 'two-hit' hypothesis has been the lack of identifiable proliferative and blocking mutations in most AML cases. However, it is now known that the CBFbeta-MYH11 fusion gene in AML and inv(16), by disrupting the normal transcription factor activity of core binding factor (CBF), functions as a class II mutation. In addition, nearly 70% of patients with AML and inv(16) are known to possess mutually exclusive mutations of the receptor tyrosine kinases (RTKs), c-KIT and FLT3, as well as RAS genes, that provide a class I, or proliferative, signal. AML and inv(16), therefore, is one of the best understood of the acute leukaemias at the genetic level and so provides a paradigm for the 'two-hit' hypothesis of leukaemogenesis. This paper reviews the recent advances in the molecular pathology of AML and inv(16) and discusses possible therapeutic implications of the current pathogenetic model.
Reilly
John T
JT
Molecular Haematology Unit, Division of Molecular and Genetic Medicine, Royal Hallamshire Hospital, Sheffield, UK. j.t.reilly@sheffield.ac.uk
D000208:Acute Disease; D000818:Animals; D007446:Chromosome Inversion; D002885:Chromosomes, Human, Pair 16; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics*; D008957:Models, Genetic; D015514:Oncogene Proteins, Fusion / Q000235:genetics
C095514:CBFbeta-MYH11 fusion protein; D015514:Oncogene Proteins, Fusion