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

• Published in: Cancer cell 2010-06, Vol.17 (6), p.609-621
• Main Authors: Muntean, Andrew G., Tan, Jiaying, Sitwala, Kajal, Huang, Yongsheng, Bronstein, Joel, Connelly, James A., Basrur, Venkatesha, Elenitoba-Johnson, Kojo S.J., Hess, Jay L.
• Format: Article
• Language: English
• Subjects: Animals; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Differentiation - genetics; Cell Line; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; CELLCYCLE; DNA; DNA - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Down-Regulation - genetics; Gene Expression Regulation; HeLa Cells; HL-60 Cells; Homeodomain Proteins - genetics; Humans; HUMDISEASE; Leukemia - genetics; Leukemia - metabolism; Mice; Mice, Inbred C57BL; Models, Biological; Myeloid Cells - cytology; Myeloid Cells - metabolism; Myeloid Ecotropic Viral Integration Site 1 Protein; Myeloid-Lymphoid Leukemia Protein - genetics; Myeloid-Lymphoid Leukemia Protein - metabolism; Neoplasm Proteins - genetics; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Phosphoproteins - genetics; Phosphoproteins - metabolism; Protein Binding - physiology; Protein Interaction Domains and Motifs - physiology; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; RNA Interference; Sequence Deletion - physiology; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic - physiology; Transcriptional Activation - genetics; Transfection; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2010.04.012

MLL 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. [Display omitted] ► 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