The elongation stage of transcription is highly regulated in metazoans. We previously purified the AFF1-and AFF4-containing super elongation complex (SEC) as a major regulator of development and cancer pathogenesis. Here, we report the biochemical isolation of SEC-like 2 (SEC-L2) and SEC-like 3 (SEC-L3) containing AFF2 and AFF3 in association with P-TEFb, ENL/MLLT1, and AF9/MLLT3. The SEC family members demonstrate high levels of polymerase II (Pol II) C-terminal domain kinase activity; however, only SEC is required for the proper induction of the HSP70 gene upon stress. Genome-wide mRNA-Seq analyses demonstrated that SEC-L2 and SEC-L3 control the expression of different subsets of genes, while AFF4/SEC plays a more dominant role in rapid transcriptional induction in cells. MYC is one of the direct targets of AFF4/SEC, and SEC recruitment to the MYC gene regulates its expression in different cancer cells, including those in acute myeloid or lymphoid leukemia. These findings suggest that AFF4/SEC could be a potential therapeutic target for the treatment of leukemia or other cancers associated with MYC overexpression.T ranscription by RNA polymerase II (Pol II) is a finely tuned and multistep process (40,42,51). After the synthesis of the first few phosphodiester bonds, RNA Pol II escapes from the promoter and enters the productive elongation stage of transcription, depending on the presence of proper environmental signals (40). For decades, the preinitiation complex (PIC) assembly was thought to be the main target of regulation during the entire transcription process. Recently, however, a large number of studies have demonstrated that in addition to the regulation of PIC, promoter-proximal pausing by Pol II and its controlled release is a major regulatory step, especially on developmentally regulated genes (3,7,27,35,38,42,43,57). Multiple elongation factors regulating the elongation stage of transcription have been identified. These include P-TEFb (positive transcription elongation factor), DSIF (DRB sensitivity-inducing factor), NELF (negative transcription elongation factor), and ELL (eleven-nineteen lysinerich leukemia gene) (21,37,40,42,43). DSIF and NELF coordinately participate in setting up paused Pol II at the promoterproximal region (50, 53). The cyclin-dependent kinase 9 (CDK9) module of the P-TEFb complex phosphorylates serine 2 of the Pol II C-terminal domain (CTD), the SPT5 subunit of DSIF, and the E subunit of NELF, leading to the dissociation of paused Pol II from DSIF and NELF for productive elongation (12,21,29,37).The kinase activity of P-TEFb is tightly regulated in vivo through the formation of different complexes to achieve its regulation of transcription elongation. The inactive form of the P-TEFb complex contains 7SK-RNA, MEPCE, LARP7, and HEXIM1, which sequester PTEFb and inhibit its kinase activity (4, 18). The vast majority of P-TEFb exists in this inactive pool (36, 55). P-TEFb was later found to form a complex with the bromodomain protein BRD4. The BRD4/ P-TEFb complex, which can phos...

The RNA polymerase II (Pol II) elongation factor (ELL) was the first translocation partner of mixed lineage leukaemia (MLL) for which a biochemical function was determined. It was therefore proposed that the regulation of the elongation stage of transcription could be fundamental to MLL-based leukaemogenesis. Recent studies have identified ELL complexed with several of the translocation partners of MLL in a transcriptional super elongation complex (SEC). These studies provide evidence for the importance of the regulation of Pol II elongation in disease pathogenesis and suggest that MLL chimaeras function by licensing Pol II transcription elongation without the appropriate checkpoints.

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