Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

NUP98–NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis

Nature Cell Biology volume 9, pages 804–812 (2007)Cite this article

Abstract

Nuclear receptor-binding SET domain protein 1 (NSD1) prototype is a family of mammalian histone methyltransferases (NSD1, NSD2/MMSET/WHSC1, NSD3/WHSC1L1) that are essential in development and are mutated in human acute myeloid leukemia (AML)1,2, overgrowth syndromes3, multiple myeloma4 and lung cancers5. In AML, the recurring t(5;11)(q35;p15.5) translocation fuses NSD1 to nucleoporin-98 (NUP98)6. Here, we present the first characterization of the transforming properties and molecular mechanisms of NUP98–NSD1. We demonstrate that NUP98–NSD1 induces AML in vivo, sustains self-renewal of myeloid stem cells in vitro, and enforces expression of the HoxA7, HoxA9, HoxA10 and Meis1 proto-oncogenes. Mechanistically, NUP98–NSD1 binds genomic elements adjacent to HoxA7 and HoxA9, maintains histone H3 Lys 36 (H3K36) methylation and histone acetylation, and prevents EZH2-mediated transcriptional repression of the Hox-A locus during differentiation. Deletion of the NUP98 FG-repeat domain, or mutations in NSD1 that inactivate the H3K36 methyltransferase activity or that prevent binding of NUP98–NSD1 to the Hox-A locus precluded both Hox-A gene activation and myeloid progenitor immortalization. We propose that NUP98–NSD1 prevents EZH2-mediated repression of Hox-A locus genes by colocalizing H3K36 methylation and histone acetylation at regulatory DNA elements. This report is the first to link deregulated H3K36 methylation to tumorigenesis and to link NSD1 to transcriptional regulation of the Hox-A locus.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: NUP98–NSD1 enforces self-renewal of myeloid progenitors and maintains expression of a subset of Hox-A genes, Meis1 and their downstream target genes.
Figure 2: NUP98–NSD1 causes AML characterized by expression of a subset of Hox-A genes and Meis1.
Figure 3: NUP98–NSD1 directly activates HoxA gene transcription and prevents H3K27-mediated represssion.
Figure 4: Analysis of NUP98-NSD1 domains required to bind chromatin activate Hox-A gene transcription and enforce myeloid progenitor self-renewal.
Figure 5: Point mutations in the NSD1 SET domain abolish upregulation of HoxA9 transcription and the ability to enforce self-renewal of myeloid progenitors.

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. La Starza, R. et al. Cryptic insertion producing two NUP98/NSD1 chimeric transcripts in adult refractory anemia with an excess of blasts. Genes Chromosomes Cancer 41, 395–399 (2004).

    Article  CAS  Google Scholar 

  2. Rosati, R. et al. NUP98 is fused to the NSD3 gene in acute myeloid leukemia associated with t(8;11)(p11.2;p15). Blood 99, 3857–3860 (2002).

    Article  CAS  Google Scholar 

  3. Tatton-Brown, K. et al. Genotype-phenotype associations in Sotos syndrome: an analysis of 266 individuals with NSD1 aberrations. Am. J. Hum. Genet. 77, 193–204 (2005).

    Article  CAS  Google Scholar 

  4. Keats, J. J. et al. Overexpression of transcripts originating from the MMSET locus characterizes all t(4;14)(p16;q32)-positive multiple myeloma patients. Blood 105, 4060–4069 (2005).

    Article  CAS  Google Scholar 

  5. Tonon, G. et al. High-resolution genomic profiles of human lung cancer. Proc. Natl Acad. Sci. USA 102, 9625–9630 (2005).

    Article  CAS  Google Scholar 

  6. Cerveira, N. et al. Frequency of NUP98–NSD1 fusion transcript in childhood acute myeloid leukaemia. Leukemia 17, 2244–2247 (2003).

    Article  CAS  Google Scholar 

  7. Sauvageau, G. et al. Differential expression of homeobox genes in functionally distinct CD34+ subpopulations of human bone marrow cells. Proc. Natl Acad. Sci. USA 91, 12223–12227 (1994).

    Article  CAS  Google Scholar 

  8. Thorsteinsdottir, U. et al. Overexpression of the myeloid leukemia-associated Hoxa9 gene in bone marrow cells induces stem cell expansion. Blood 99, 121–129 (2002).

    Article  CAS  Google Scholar 

  9. Lawrence, H. J. et al. Frequent co-expression of the HOXA9 and MEIS1 homeobox genes in human myeloid leukemias. Leukemia 13, 1993–1999 (1999).

    Article  CAS  Google Scholar 

  10. Afonja, O. et al. MEIS1 and HOXA7 genes in human acute myeloid leukemia. Leuk. Res. 24, 849–855 (2000).

    Article  CAS  Google Scholar 

  11. Kroon, E. et al. Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b. EMBO J. 17, 3714–3725 (1998).

    Article  CAS  Google Scholar 

  12. Wang, G. G., Pasillas, M. P. & Kamps, M. P. Persistent transactivation by meis1 replaces hox function in myeloid leukemogenesis models: evidence for co-occupancy of meis1–pbx and hox–pbx complexes on promoters of leukemia-associated genes. Mol. Cell Biol. 26, 3902–3916 (2006).

    Article  CAS  Google Scholar 

  13. Hess, J. L. MLL: a histone methyltransferase disrupted in leukemia. Trends Mol. Med. 10, 500–507 (2004).

    Article  CAS  Google Scholar 

  14. Wysocka, J. et al. WDR5 associates with histone H3 methylated at K4 and is essential for H3 K4 methylation and vertebrate development. Cell 121, 859–872 (2005).

    Article  CAS  Google Scholar 

  15. Dou, Y. et al. Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF. Cell 121, 873–885 (2005).

    Article  CAS  Google Scholar 

  16. Yokoyama, A. et al. The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis. Cell 123, 207–218 (2005).

    Article  CAS  Google Scholar 

  17. Okada, Y. et al. hDOT1L links histone methylation to leukemogenesis. Cell 121, 167–178 (2005).

    Article  CAS  Google Scholar 

  18. Okada, Y. et al. Leukaemic transformation by CALM–AF10 involves upregulation of Hoxa5 by hDOT1L. Nature Cell Biol. 8, 1017–1024 (2006).

    Article  CAS  Google Scholar 

  19. Milne, T. A., Martin, M. E., Brock, H. W., Slany, R. K. & Hess, J. L. Leukemogenic MLL fusion proteins bind across a broad region of the Hox a9 locus, promoting transcription and multiple histone modifications. Cancer Res. 65, 11367–11374 (2005).

    Article  CAS  Google Scholar 

  20. Kasper, L. H. et al. CREB binding protein interacts with nucleoporin-specific FG repeats that activate transcription and mediate NUP98–HOXA9 oncogenicity. Mol. Cell Biol. 19, 764–776 (1999).

    Article  CAS  Google Scholar 

  21. Rayasam, G. V. et al. NSD1 is essential for early post-implantation development and has a catalytically active SET domain. EMBO J. 22, 3153–3163 (2003).

    Article  CAS  Google Scholar 

  22. Pokholok, D. K. et al. Genome-wide map of nucleosome acetylation and methylation in yeast. Cell 122, 517–527 (2005).

    Article  CAS  Google Scholar 

  23. Xiao, T. et al. Phosphorylation of RNA polymerase II CTD regulates H3 methylation in yeast. Genes Dev. 17, 654–663 (2003).

    Article  CAS  Google Scholar 

  24. Tompa, R. & Madhani, H. D. Histone H3 lysine 36 methylation antagonizes silencing in Saccharomyces cerevisiae independently of the Rpd3S histone deacetylase complex. Genetics 175, 585–593 (2007).

    Article  CAS  Google Scholar 

  25. Carrozza, M. J. et al. Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription. Cell 123, 581–592 (2005).

    Article  CAS  Google Scholar 

  26. Zhao, Z., Yu, Y., Meyer, D., Wu, C. & Shen, W. H. Prevention of early flowering by expression of FLOWERING LOCUS C requires methylation of histone H3 K36. Nature Cell Biol. 7, 1256–1260 (2005).

    Article  Google Scholar 

  27. Bender, L. B. et al. MES-4: an autosome-associated histone methyltransferase that participates in silencing the X chromosomes in the C. elegans germ line. Development 133, 3907–3917 (2006).

    Article  CAS  Google Scholar 

  28. Fong, Y., Bender, L., Wang, W. & Strome, S. Regulation of the different chromatin states of autosomes and X chromosomes in the germ line of C. elegans. Science 296, 2235–2238 (2002).

    Article  CAS  Google Scholar 

  29. Wang, G. G., Pasillas, M. P. & Kamps, M. P. Meis1 programs transcription of FLT3 and cancer stem cell character, using a mechanism that requires interaction with PBX and a novel function of the Meis1 C-terminus. Blood 106, 254–264 (2005).

    Article  CAS  Google Scholar 

  30. Wang, G. G. et al. Quantitative production of macrophages or neutrophils ex vivo using conditional Hoxb8. Nature Methods 3, 287–293 (2006).

    Article  CAS  Google Scholar 

  31. Zeisig, B. B. et al. Hoxa9 and Meis1 are key targets for MLL-ENL-mediated cellular immortalization. Mol. Cell Biol. 24, 617–628 (2004).

    Article  CAS  Google Scholar 

  32. Cao, R. & Zhang, Y. SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED–EZH2 complex. Mol. Cell 15, 57–67 (2004).

    Article  CAS  Google Scholar 

  33. Cha, T. L. et al. Akt-mediated phosphorylation of EZH2 suppresses methylation of lysine 27 in histone H3. Science 310, 306–310 (2005).

    Article  CAS  Google Scholar 

  34. Wysocka, J. et al. A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature 442, 86–90 (2006).

    Article  CAS  Google Scholar 

  35. Shi, X. et al. ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature 442, 96–99 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work is supported by Public Health Service grant NIH CA56876 awarded to M.P.K. We thank D. Young for assistance with FACS analysis, J. Aguilera for assistance with mouse radiation and C. Yost for assistance with haematological analysis (UCSD Cancer Center Shared Resources). Special thanks to P. Chambon, J. Van Deursen and R. Slany for providing plasmids and antibodies. We also thank J.-L. Luo and S. Zhang for helping with bone marrow transplantation and fluorescence microscopy.

Author information

Authors and Affiliations

  1. Department of Pathology, University of California at San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, 92093, CA, USA

    Gang G. Wang, Martina P. Pasillas & Mark P. Kamps

  2. Biomedical Sciences Graduate Program, University of California at San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, 92093, CA, USA

    Gang G. Wang & Mark P. Kamps

  3. Division of Biological Sciences, University of California at San Diego, 9500 Gilman Drive, La Jolla, 92093, CA, USA

    Ling Cai

Authors
  1. Gang G. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ling Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martina P. Pasillas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mark P. Kamps
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark P. Kamps.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary figures S1, S2, S3, S4 and Supplementary table S1 (PDF 442 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, G., Cai, L., Pasillas, M. et al. NUP98–NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. Nat Cell Biol 9, 804–812 (2007). https://doi.org/10.1038/ncb1608

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1608

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing