Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Shilatifard, A., Lane, W. S., Jackson, K. W., Conaway, R. C. & Conaway, J. W. An RNA polymerase II elongation factor encoded by the human ELL gene. Science 271, 1873–1876 (1996).
Shilatifard, A. Factors regulating the transcriptional elongation activity of RNA polymerase II. FASEB J. 12, 1437–1446 (1998).
Meyer, C. et al. New insights to the MLL recombinome of acute leukemias. Leukemia 23, 1490–1499 (2009).
Krogan, N. J. et al. COMPASS, a histone H3 (Lysine 4) methyltransferase required for telomeric silencing of gene expression. J. Biol. Chem. 277, 10753–10755 (2002).
Miller, T. et al. COMPASS: a complex of proteins associated with a trithorax-related SET domain protein. Proc. Natl Acad. Sci. USA 98, 12902–12907 (2001).
Roguev, A. et al. The Saccharomyces cerevisiae Set1 complex includes an Ash2 homologue and methylates histone 3 lysine 4. EMBO J. 20, 7137–7148 (2001).
Shilatifard, A. Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression. Annu. Rev. Biochem. 75, 243–269 (2006).
Eissenberg, J. C. & Shilatifard, A. Histone H3 lysine 4 (H3K4) methylation in development and differentiation. Dev. Biol. 339, 240–249 (2010).
Hughes, C. M. et al. Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. Mol. Cell 13, 587–597 (2004).
Yokoyama, A. et al. Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression. Mol. Cell. Biol. 24, 5639–5649 (2004).
Wang, P. et al. Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL-mediated H3K4 methylation in the regulation of transcriptional initiation by RNA polymerase II. Mol. Cell. Biol. 29, 6074–6085 (2009).
Wang, Y. et al. The Wnt/β-catenin pathway is required for the development of leukemia stem cells in AML. Science 327, 1650–1653 (2010).
He, N. et al. HIV-1 Tat and host AFF4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of HIV-1 transcription. Mol. Cell 38, 428–438 (2010).
Lin, C. et al. AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. Mol. Cell 37, 429–437 (2010).
Sobhian, B. et al. HIV-1 Tat assembles a multifunctional transcription elongation complex and stably associates with the 7SK snRNP. Mol. Cell 38, 439–451 (2010).
Mohan, M. et al. Linking H3K79 trimethylation to Wnt signaling through a novel Dot1-containing complex (DotCom). Genes Dev. 24, 574–589 (2010).
Djabali, M. et al. A trithorax-like gene is interrupted by chromosome 11q23 translocations in acute leukaemias. Nature Genet. 2, 113–118 (1992).
Gu, Y. et al. The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene. Cell 71, 701–708 (1992).
Tkachuk, D. C., Kohler, S. & Cleary, M. L. Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias. Cell 71, 691–700 (1992).
Chessells, J. M. et al. Clinical features, cytogenetics and outcome in acute lymphoblastic and myeloid leukaemia of infancy: report from the MRC Childhood Leukaemia working party. Leukemia 16, 776–784 (2002).
Hilden, J. M. et al. Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children's Oncology Group. Blood 108, 441–451 (2006).
Pieters, R. et al. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet 370, 240–250 (2007).
Tomizawa, D. et al. Outcome of risk-based therapy for infant acute lymphoblastic leukemia with or without an MLL gene rearrangement, with emphasis on late effects: a final report of two consecutive studies, MLL96 and MLL98, of the Japan Infant Leukemia Study Group. Leukemia 21, 2258–2263 (2007).
van der Linden, M. H. et al. Outcome of congenital acute lymphoblastic leukemia treated on the Interfant-99 protocol. Blood 114, 3764–3768 (2009).
Raimondi, S. C. et al. Chromosomal abnormalities in 478 children with acute myeloid leukemia: clinical characteristics and treatment outcome in a cooperative pediatric oncology group study-POG 8821. Blood 94, 3707–3716 (1999).
Schoch, C. et al. AML with 11q23/MLL abnormalities as defined by the WHO classification: incidence, partner chromosomes, FAB subtype, age distribution, and prognostic impact in an unselected series of 1897 cytogenetically analyzed AML cases. Blood 102, 2395–2402 (2003).
Corral, J. et al. An Mll-AF9 fusion gene made by homologous recombination causes acute leukemia in chimeric mice: a method to create fusion oncogenes. Cell 85, 853–861 (1996).
Rowley, J. D. The critical role of chromosome translocations in human leukemias. Annu. Rev. Genet. 32, 495–519 (1998).
So, C. W. et al. MLL-GAS7 transforms multipotent hematopoietic progenitors and induces mixed lineage leukemias in mice. Cancer Cell 3, 161–171 (2003).
Martin, M. E. et al. Dimerization of MLL fusion proteins immortalizes hematopoietic cells. Cancer Cell 4, 197–207 (2003).
So, C. W., Lin, M., Ayton, P. M., Chen, E. H. & Cleary, M. L. Dimerization contributes to oncogenic activation of MLL chimeras in acute leukemias. Cancer Cell 4, 99–110 (2003).
Moghrabi, A. et al. Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95–01 for children with acute lymphoblastic leukemia. Blood 109, 896–904 (2007).
Moricke, A. et al. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 111, 4477–4489 (2008).
Stark, B. et al. Classical and molecular cytogenetic abnormalities and outcome of childhood acute myeloid leukaemia: report from a referral centre in Israel. Br. J. Haematol. 126, 320–337 (2004).
Krauter, J. et al. Prognostic factors in adult patients up to 60 years old with acute myeloid leukemia and translocations of chromosome band 11q23: individual patient data-based meta-analysis of the German Acute Myeloid Leukemia Intergroup. J. Clin. Oncol. 27, 3000–3006 (2009).
Lie, S. O. et al. Treatment stratification based on initial in vivo response in acute myeloid leukaemia in children without Down's syndrome: results of NOPHO-AML trials. Br. J. Haematol. 122, 217–225 (2003).
Mrozek, K. et al. Adult patients with de novo acute myeloid leukemia and t(9; 11)(p22; q23) have a superior outcome to patients with other translocations involving band 11q23: a cancer and leukemia group B study. Blood 90, 4532–4538 (1997).
Rubnitz, J. E. et al. Favorable impact of the t(9;11) in childhood acute myeloid leukemia. J. Clin. Oncol. 20, 2302–2309 (2002).
Pui, C. H. et al. Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region. Lancet 359, 1909–1915 (2002).
Ingham, P. W. & Whittle, R. Trithorax: a new homeotic mutation of Drosophila melanogaster causing transformations of abdominal and thoracic imaginal segments. Mol. Gen. Genet. 179, 607–614 (1980).
Ringrose, L. & Paro, R. Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu. Rev. Genet. 38, 413–443 (2004).
Shilatifard, A. Molecular implementation and physiological roles for histone H3 lysine 4 (H3K4) methylation. Curr. Opin. Cell Biol. 20, 341–348 (2008).
Schneider, J. et al. Molecular regulation of histone H3 trimethylation by COMPASS and the regulation of gene expression. Mol. Cell 19, 849–856 (2005).
Steward, M. M. et al. Molecular regulation of H3K4 trimethylation by ASH2L, a shared subunit of MLL complexes. Nature Struct. Mol. Biol. 13, 852–854 (2006).
Yokoyama, A. & Cleary, M. L. Menin critically links MLL proteins with LEDGF on cancer-associated target genes. Cancer Cell 14, 36–46 (2008).
Chandrasekharappa, S. C. et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 276, 404–407 (1997).
Hsieh, J. J., Ernst, P., Erdjument-Bromage, H., Tempst, P. & Korsmeyer, S. J. Proteolytic cleavage of MLL generates a complex of N- and C-terminal fragments that confers protein stability and subnuclear localization. Mol. Cell. Biol. 23, 186–194 (2003).
Yokoyama, A., Kitabayashi, I., Ayton, P. M., Cleary, M. L. & Ohki, M. Leukemia proto-oncoprotein MLL is proteolytically processed into 2 fragments with opposite transcriptional properties. Blood 100, 3710–3718 (2002).
Birke, M. et al. The Montana domain of the proto-oncoprotein MLL binds to CpG-containing DNA and discriminates against methylation. Nucleic Acids Res. 30, 958–965 (2002).
Slany, R. K., Lavau, C. & Cleary, M. L. The oncogenic capacity of HRX-ENL requires the transcriptional transactivation activity of ENL and the DNA binding motifs of HRX. Mol. Cell. Biol. 18, 122–129 (1998).
Zeleznik-Le, N. J., Harden, A. M. & Rowley, J. D. 11q23 translocations split the “AT-hook” cruciform DNA-binding region and the transcriptional repression domain from the activation domain of the mixed-lineage leukemia (MLL) gene. Proc. Natl Acad. Sci. USA 91, 10610–10614 (1994).
Thiel, A. T. et al. MLL-AF9-induced leukemogenesis requires coexpression of the wild-type Mll allele. Cancer Cell 17, 148–159 (2010).
Yokoyama, A., Lin, M., Naresh, A., Kitabayashi, I. & Cleary, M. L. A higher-order complex containing AF4 and ENL family proteins with P-TEFb facilitates oncogenic and physiologic MLL-dependent transcription. Cancer Cell 17, 198–212 (2010).
Mueller, D. et al. A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification. Blood 110, 4445–4454 (2007).
Miller, T., Williams, K., Johnstone, R. W. & Shilatifard, A. Identification, cloning, expression, and biochemical characterization of the testis-specific RNA polymerase II elongation factor ELL3. J. Biol. Chem. 275, 32052–32056 (2000).
Shilatifard, A. et al. ELL2, a new member of an ELL family of RNA polymerase II elongation factors. Proc. Natl Acad. Sci. USA 94, 3639–3643 (1997).
DiMartino, J. F. et al. A carboxy-terminal domain of ELL is required and sufficient for immortalization of myeloid progenitors by MLL-ELL. Blood 96, 3887–3893 (2000).
Eissenberg, J. C. et al. dELL is an essential RNA polymerase II elongation factor with a general role in development. Proc. Natl Acad. Sci. USA 99, 9894–9899 (2002).
Gerber, M., Ma, J., Dean, K., Eissenberg, J. C. & Shilatifard, A. Drosophila ELL is associated with actively elongating RNA polymerase II on transcriptionally active sites in vivo. EMBO J. 20, 6104–6114 (2001).
Smith, E. R., Winter, B., Eissenberg, J. C. & Shilatifard, A. Regulation of the transcriptional activity of poised RNA polymerase II by the elongation factor ELL. Proc. Natl Acad. Sci. USA 105, 8575–8579 (2008).
Schulze, J. M., Wang, A. Y. & Kobor, M. S. YEATS domain proteins: a diverse family with many links to chromatin modification and transcription. Biochem. Cell Biol. 87, 65–75 (2009).
Bitoun, E., Oliver, P. L. & Davies, K. E. The mixed-lineage leukemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling. Hum. Mol. Genet. 16, 92–106 (2007).
Estable, M. C. et al. MCEF, the newest member of the AF4 family of transcription factors involved in leukemia, is a positive transcription elongation factor-b-associated protein. J. Biomed. Sci. 9, 234–245 (2002).
Boettiger, A. N. & Levine, M. Synchronous and stochastic patterns of gene activation in the Drosophila embryo. Science 325, 471–473 (2009).
Muse, G. W. et al. RNA polymerase is poised for activation across the genome. Nature Genet. 39, 1507–1511 (2007).
Zeitlinger, J. et al. RNA polymerase stalling at developmental control genes in the Drosophila melanogaster embryo. Nature Genet. 39, 1512–1516 (2007).
Peterlin, B. M. & Price, D. H. Controlling the elongation phase of transcription with P-TEFb. Mol. Cell 23, 297–305 (2006).
Okada, Y. et al. hDOT1L links histone methylation to leukemogenesis. Cell 121, 167–178 (2005).
Lacoste, N., Utley, R. T., Hunter, J. M., Poirier, G. G. & Cote, J. Disruptor of telomeric silencing-1 is a chromatin-specific histone H3 methyltransferase. J. Biol. Chem. 277, 30421–30424 (2002).
Ng, H. H., Xu, R. M., Zhang, Y. & Struhl, K. Ubiquitination of histone H2B by Rad6 is required for efficient Dot1-mediated methylation of histone H3 lysine 79. J. Biol. Chem. 277, 34655–34657 (2002).
van Leeuwen, F., Gafken, P. R. & Gottschling, D. E. Dot1p modulates silencing in yeast by methylation of the nucleosome core. Cell 109, 745–756 (2002).
Im, H. et al. Dynamic regulation of histone H3 methylated at lysine 79 within a tissue-specific chromatin domain. J. Biol. Chem. 278, 18346–18352 (2003).
Schubeler, D. et al. The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote. Genes Dev. 18, 1263–1271 (2004).
Barski, A. et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007).
Schulze, J. M. et al. Linking cell cycle to histone modifications: SBF and H2B monoubiquitination machinery and cell-cycle regulation of H3K79 dimethylation. Mol. Cell 35, 626–641 (2009).
Krivtsov, A. V. et al. H3K79 methylation profiles define murine and human MLL-AF4 leukemias. Cancer Cell 14, 355–368 (2008).
Goessling, W. et al. APC mutant zebrafish uncover a changing temporal requirement for wnt signaling in liver development. Dev. Biol. 320, 161–174 (2008).
Gregorieff, A. & Clevers, H. Wnt signaling in the intestinal epithelium: from endoderm to cancer. Genes Dev. 19, 877–890 (2005).
Karim, R., Tse, G., Putti, T., Scolyer, R. & Lee, S. The significance of the Wnt pathway in the pathology of human cancers. Pathology 36, 120–128 (2004).
Mosimann, C., Hausmann, G. & Basler, K. β-catenin hits chromatin: regulation of Wnt target gene activation. Nature Rev. Mol. Cell Biol. 10, 276–286 (2009).
Sierra, J., Yoshida, T., Joazeiro, C. A. & Jones, K. A. The APC tumor suppressor counteracts β-catenin activation and H3K4 methylation at Wnt target genes. Genes Dev. 20, 586–600 (2006).
Reya, T. & Clevers, H. Wnt signalling in stem cells and cancer. Nature 434, 843–850 (2005).
MacDonald, B. T., Tamai, K. & He, X. Wnt/β-catenin signaling: components, mechanisms, and diseases. Dev. Cell 17, 9–26 (2009).
Krogan, N. J. et al. The Paf1 complex is required for histone H3 methylation by COMPASS and Dot1p: linking transcriptional elongation to histone methylation. Mol. Cell 11, 721–729 (2003).
Ng, H. H., Robert, F., Young, R. A. & Struhl, K. Targeted recruitment of Set1 histone methylase by elongating Pol. II provides a localized mark and memory of recent transcriptional activity. Mol. Cell 11, 709–719 (2003).
Vermeulen, M. et al. Selective anchoring of TFIID to nucleosomes by trimethylation of histone H3 lysine 4. Cell 131, 58–69 (2007).
Shah, N. & Sukumar, S. The Hox genes and their roles in oncogenesis. Nature Rev. Cancer 10, 361–371 (2010).
Kroon, E. et al. Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b. EMBO J. 17, 3714–3725 (1998).
Margaritis, T. & Holstege, F. C. Poised RNA polymerase II gives pause for thought. Cell 133, 581–584 (2008).
Shilatifard, A., Conaway, R. C. & Conaway, J. W. The RNA polymerase II elongation complex. Annu. Rev. Biochem. 72, 693–715 (2003).
Acknowledgements
The authors would like to thank E. Smith, A. Gamis and E. Park for conversations, suggestions and critical reading of the manuscript. They also thank L. Shilatifard for editorial assistance. C.L. is a graduate student registered with the Open University. The studies in the Shilatifard laboratory are supported in part by grants from Alex's Lemonade Stand Foundation to E.G. and from the US National Institute of Health grants R01GM069905, R01CA150265 and R01CA89455 to A.S.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
Glossary
- Multidimensional protein identification technology
-
(MudPIT). This is a sensitive mass spectrometric method used for the identification of complex mixtures of proteins.
- YEATS domain
-
The YEATS domain proteins are a diverse family of proteins conserved from yeast to human, which function in chromatin modifications and remodelling, and transcriptional regulation. The name for this family of proteins is derived from the first five proteins (YAF9, ENL, AF9, TAF14 and SAS5) that were discovered to have this domain.
Rights and permissions
About this article
Cite this article
Mohan, M., Lin, C., Guest, E. et al. Licensed to elongate: a molecular mechanism for MLL-based leukaemogenesis. Nat Rev Cancer 10, 721–728 (2010). https://doi.org/10.1038/nrc2915
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrc2915
This article is cited by
-
Epigenetic drug screening for trophoblast syncytialization reveals a novel role for MLL1 in regulating fetoplacental growth
BMC Medicine (2024)
-
Mapping AML heterogeneity - multi-cohort transcriptomic analysis identifies novel clusters and divergent ex-vivo drug responses
Leukemia (2024)
-
Post-translational modification-dependent oligomerization switch in regulation of global transcription and DNA damage repair during genotoxic stress
Nature Communications (2024)
-
COMPASS and SWI/SNF complexes in development and disease
Nature Reviews Genetics (2021)
-
A novel deletion mutation in KMT2A identified in a child with ID/DD and blood eosinophilia
BMC Medical Genetics (2019)