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

Abstract

Summary 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 post-translational histone modifications. PAFc augments MLL and MLL-AF9 mediated transcriptional activation of Hoxa9. Conversely, knock down of PAFc disrupts MLL fusion protein-mediated transcriptional activation and MLL recruitment to target loci. PAFc gene expression is down regulated 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.

TET1 plays an essential oncogenic role in MLL -rearranged leukemia

“…MLL has around 100 different partners, and the functions of some of them have been identified (30,52). MLL itself is a large multifunctional protein (homolog of Drosophila trithorax) with many functions related to chromatin structure; many of MLL's partners are members of chromatin-modifying complexes including ENL, AF9, AF4, and AF10, which interact with DOT1L, and ELL, AF4/FMR2 family member 1 (AFF1), and AFF4, which interact with positive transcription elongation factor b (P-TEFb) (37,(53)(54)(55)(56). Thus, a fusion protein consisting of MLL and one of the members of the complexes would be much more effective in promoting regulation of critical targets and enhancing cell proliferation than the two proteins produced independently in the cell and meeting at a critical location by chance.…”

Disordered epigenetic regulation in MLL-related leukemia

“…MLL-Menin-LEDGE complex is critical for the proper targeting of MLL or MLL fusion proteins to specific target genes [17]. Recently, another important complex, the Polymerase Associated Factor complex (PAFc), has been found to interact with CxxC-RD2 region in MLL [18,19]. PAFc plays important roles in a wide range of biological processes, including the initiation, elongation, and termination of gene transcription, cell cycle regulation, mRNA processing, H2B monoubiquitination (cooperating with BRE1/RAD6 complex), H3K4 methylation and H3K79 methylation (cooperating with DOT1L) [20].…”

“…PAFc plays important roles in a wide range of biological processes, including the initiation, elongation, and termination of gene transcription, cell cycle regulation, mRNA processing, H2B monoubiquitination (cooperating with BRE1/RAD6 complex), H3K4 methylation and H3K79 methylation (cooperating with DOT1L) [20]. PAFc-MLL interaction is critical for transcriptional activation of MLL and MLL fusions, and is essential for MLL fusion-mediated leukemogenesis [18].…”

Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia

“…3,[5][6][7] Two regions in this fragment of MLL have been shown to be indispensable for leukemogenic transformation: the N-terminal region, which binds to menin 8 and to lens epithelium-derived growth factor (LEDGF), 9 and the conserved region encompassing the CXXC domain, which mediates binding to nonmethylated CpG DNA [10][11][12] and interacts with the polymerase associated factor complex (PAFc). 13,14 Targeting these interactions provides new opportunities for the development of new therapeutic agents for the MLL leukemias. 15 Menin is a tumor-suppressor protein encoded by the MEN1 (multiple endocrine neoplasia 1) gene.…”