The PAF Complex Synergizes with MLL Fusion Proteins at HOX Loci to Promote Leukemogenesis

SummaryMLL is involved in chromosomal rearrangements that generate fusion proteins with deregulated transcriptional activity. The mechanisms of MLL fusion protein-mediated transcriptional activation are poorly understood. Here we show MLL interacts directly with the polymerase associated factor complex (PAFc) through sequences flanking the CxxC domain. PAFc interacts with RNA polymerase II and stimulates posttranslational histone modifications. PAFc augments MLL and MLL-AF9 mediated transcriptional activation of Hoxa9. Conversely, knockdown of PAFc disrupts MLL fusion protein-mediated transcriptional activation and MLL recruitment to target loci. PAFc gene expression is downregulated during hematopoiesis and likely serves to regulate MLL function. Deletions of MLL that abolish interactions with PAFc also eliminate MLL-AF9 mediated immortalization indicating an essential function for this interaction in leukemogenesis.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (286 K)Download as PowerPoint slideHighlights► PAFc interacts with the pre-CxxC and RD2 domains of MLL ► Transcriptional activity of MLL and MLL fusion proteins is stimulated by PAFc ► MLL fusion protein mediated transformation is dependent upon interaction with PAFc ► PAFc expression is coordinately downregulated during myeloid differentiation