Disruption of differentiation in human cancer: AML shows the way

Key Points Loss of differentiation is an important component in the pathogenesis of many cancers. Acute myeloid leukaemia (AML) represents a salient example of a cancer that is characterized by a differentiation block. Specific haematopoietic transcription factors are crucial for differentiation to particular lineages during normal differentiation, and are controlled by specific patterns of expression and protein interactions. These same transcription factors are frequently disrupted in AML. Some mechanisms of disruption involve the effect of fusion proteins that are generated by chromosomal translocations on haematopoietic transcription factors. In other cases, in the absence of common translocations, the transcription factors themselves are mutated. Characterizing these transcription-factor abnormalities has already affected classification schemes based on patient outcome. These transcription-factor pathways represent important targets for therapeutic intervention. Although much is understood about the ways in which transcription factors regulate various differentiation systems, and one of the hallmarks of many human cancers is a lack of cellular differentiation, relatively few reports have linked these two processes. Recent studies of acute myeloid leukaemia (AML), however, have indicated how disruption of transcription-factor function can disrupt normal cellular differentiation and lead to cancer. This model involves lineage-specific transcription factors, which are involved in normal haematopoietic differentiation. These factors are often targeted in AML — either by direct mutation or by interference from translocation proteins. Uncovering these underlying pathways will improve the diagnosis and treatment of AML, and provide a working model for other types of human cancer, including solid tumours.