A Higher-Order Complex Containing AF4 and ENL Family Proteins with P-TEFb Facilitates Oncogenic and Physiologic MLL-Dependent Transcription

SummaryAF4 and ENL family proteins are frequently fused with MLL, and they comprise a higher order complex (designated AEP) containing the P-TEFb transcription elongation factor. Here, we show that AEP is normally recruited to MLL-target chromatin to facilitate transcription. In contrast, MLL oncoproteins fused with AEP components constitutively form MLL/AEP hybrid complexes to cause sustained target gene expression, which leads to transformation of hematopoietic progenitors. Furthermore, MLL-AF6, an MLL fusion with a cytoplasmic protein, does not form such hybrid complexes, but nevertheless constitutively recruits AEP to target chromatin via unknown alternative mechanisms. Thus, AEP recruitment is an integral part of both physiological and pathological MLL-dependent transcriptional pathways. Bypass of its normal recruitment mechanisms is the strategy most frequently used by MLL oncoproteins.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (282 K)Download as PowerPoint slideHighlights► Proteins of the AF4 and ENL families form a complex (AEP) with P-TEFb on chromatin ► The AEP complex facilitates physiologic MLL target gene expression ► Aberrant AEP recruitment is a unifying mechanism in MLL-mediated leukemogenesis