ReviewTranscriptional activation by MLL fusion proteins in leukemogenesis

•MLL gene rearrangements cause acute leukemia by constitutive activation of self-renewal-related genes.•MLL fusion proteins target the promoter proximal regions of previously-active CpG-rich genes.•TBP loading through SL1 is the rate-limiting step regulated by MLL-AEP fusion proteins.•Recruitment of transcription elongation and mediator activities by MLL fusion proteins is not essential for leukemogenesis.

Chromosomal translocations involving the mixed lineage leukemia (MLL) gene cause aggressive leukemia. Fusion proteins of MLL and a component of the AF4 family/ENL family/P-TEFb complex (AEP) are responsible for two-thirds of MLL-associated leukemia cases. MLL-AEP fusion proteins trigger aberrant self-renewal of hematopoietic progenitors by constitutively activating self-renewal-related genes. MLL-AEP fusion proteins activate transcription initiation by loading the TATA-binding protein (TBP) to the TATA element via selectivity factor 1. Although AEP retains transcription elongation and mediator recruiting activities, the rate-limiting step activated by MLL-AEP fusion proteins appears to be the TBP-loading step. This is contrary to prevailing views, in which the recruitment of transcription elongation activities are emphasized. Here, I review recent advances towards elucidating the mechanisms underlying gene activation by MLL-AEP fusion proteins in leukemogenesis.

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