General mechanisms for oncogenic activation of chimeric transcription factors by dimerization/oligomerization in acute leukemias. (A) Forced homotypic interactions mediated by the fusion partner trap the DNA-binding component of the chimera in a conformation with altered association for transcriptional cofactors. For RARα, the cofactors mediate transcriptional repression, but, for dimerized MLL fusion proteins, they likely mediate activation. (B) In a second mechanistic category, the dimerization/oligomerization moiety itself serves as a platform for recruitment of transcriptional cofactors, as best illustrated by AML1 fusion proteins. This scenario relies on conformational features of the dimerization moiety that favor preferential assembly of corepressors (or coactivators) on multimerized protein interfaces. (C) A third mechanistic category invokes competitive sequestration of a DNA-binding partner (eg, AML1) by the oligomerized chimera, a model proposed for the potential role of CBFβ/SMMHC. Undoubtedly, some chimeras simultaneously function through more than one of these mechanisms. Examples are the dual roles of PLZF/RARα, Stat5b/RARα, and possibly CBFβ/SMMHC.