AFF4, a Component of the ELL/P-TEFb Elongation Complex and a Shared Subunit of MLL Chimeras, Can Link Transcription Elongation to Leukemia

Abstract

Chromosomal translocations involving the MLL gene are associated with infant acute lymphoblastic and mixed lineage leukemia. There are a large number of translocation partners of MLL that share very little sequence or seemingly functional similarities, however, their translocations into MLL result in the pathogenesis of leukemia. To define the molecular reason why these translocations result in the pathogenesis of leukemia, we purified several of the commonly occurring MLL chimeras. We have identified a novel super elongation complex (SEC) associated with all chimeras purified. SEC includes ELL, P-TEFb, AFF4 and several other factors. AFF4 is required for SEC stability and proper transcription by poised RNA polymerase II in metazoans. Knockdown of AFF4 within SEC in leukemic cells shows reduction in MLL chimera target gene expression suggesting that AFF4/SEC could be a key regulator in the pathogenesis of leukemia through many of the MLL partners.

Serine-7 but not serine-5 phosphorylation primes RNA polymerase II CTD for P-TEFb recognition

“…Finally, we investigated the effect of human AFF4 on the activity of P-TEFb. AFF4 is a subunit of the super elongation complex that is recruited by mixed lineage leukaemia (MLL) proteins to activate the expression of MLL target genes [35][36][37][38] . The N-terminal 300 amino acids of AFF4 were shown to specifically interact with P-TEFb 39,40 .…”

p53 represses the transcription of snRNA genes by preventing the formation of little elongation complex

“…SEC plays a role in the proper coordinated induction of Hox genes during early developmental stages and is also involved in the misregulation of Hox genes in leukemia [30][31][32][33][34]. If p53 can also interact with ELL in SEC, it may inhibit the formation of SEC as well.…”

The essential role of acetyllysine binding by the YEATS domain in transcriptional regulation

“…12 Early studies in mice implicated AF9 in normal embryonic development possibly through regulation of HOX gene expression, 13 and recent ChIP-seq analysis revealed that AF9 is recruited to H3K9ac-enriched loci near the HOX gene cluster in cancer cells. 3 AF9 is found to associate with several nuclear complexes, most notably the SEC, [14][15][16] and separately with the histone H3K79-specific methyltransferase DOT1L. 3,17,18 DOT1L-mediated H3K79 methylation is strongly linked to active gene expression, suggesting that interaction of AF9 with DOT1L may play a role in DOT1L recruitment to gene promoters and transcriptional activation.…”