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.

Acute Myeloid Leukemia

Tip60 activates Hoxa9 and Meis1 expression through acetylation of H2A.Z, promoting MLL-AF10 and MLL-ENL acute myeloid leukemia

Abstract

Chromosome translocations involving the MLL gene are common rearrangements in leukemia. Such translocations fuse the MLL 5’-region to partner genes in frame, producing MLL-fusions that cause MLL-related leukemia. MLL-fusions activate transcription of target genes such as HoxA cluster and Meis1, but the underlying mechanisms remain to be fully elucidated. In this study, we discovered that Tip60, a MYST-type histone acetyltransferase, was required for the expression of HoxA cluster and Meis1 genes and the development of MLL-fusion leukemia. Tip60 was recruited by MLL-AF10 and MLL-ENL fusions to the Hoxa9 locus, where it acetylated H2A.Z, thereby promoting Hoxa9 gene expression. Conditional deletion of Tip60 prevented the development of MLL-AF10 and MLL-ENL leukemia, indicating that Tip60 is indispensable for the leukemogenic activity of the MLL-AF10 and MLL-ENL-fusions. Our findings provide novel insight about epigenetic regulation in the development of MLL-AF10 and MLL-ENL-fusion leukemia.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: MLL-AF10 positively regulates the ratio of acetylated H2A.Z to total H2A.Z on the Hoxa9 locus.
Fig. 2: Tip60 acetylates H2A.Z.
Fig. 3: Tip60 colocalizes with MLL-AF10 and MLL-ENL at Hoxa9 locus.
Fig. 4: Tip60 is essential for MLL-AF10 and MLL-ENL-transformed cells in vitro.
Fig. 5: Tip60 is required for development of MLL-AF10 and MLL-ENL leukemia in vivo.
Fig. 6: Tip60 globally regulates MLL-AF10 target genes.

References

  1. 1.

    Krivtsov AV, Armstrong SA. MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer. 2007;7:823–33.

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Jude CD, Climer L, Xu D, Artinger E, Fisher JK, Ernst P. Unique and independent roles for MLL in adult hematopoietic stem cells and progenitors. Cell Stem Cell. 2007;1:324–37.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Bernt KM, Zhu N, Sinha AU, Vempati S, Faber J, Krivtsov AV, et al. MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell. 2011;20:66–78.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Chen CW, Armstrong SA. Targeting DOT1L and HOX gene expression in MLL-rearranged leukemia and beyond. Exp Hematol. 2015;43:673–84.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Yokoyama A, Lin M, Naresh A, Kitabayashi I, Cleary ML. A higher-order complex containing AF4 and ENL family proteins with P-TEFb facilitates oncogenic and physiologic MLL-dependent transcription. Cancer Cell. 2010;17:198–212.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Tan J, Jones M, Koseki H, Nakayama M, Muntean AG, Maillard I, et al. CBX8, a polycomb group protein, is essential for MLL-AF9-induced leukemogenesis. Cancer Cell. 2011;20:563–75.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Maethner E, Garcia-Cuellar MP, Breitinger C, Takacova S, Divoky V, Hess JL, et al. MLL-ENL inhibits polycomb repressive complex 1 to achieve efficient transformation of hematopoietic cells. Cell Rep. 2013;3:1553–66.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Zeisig BB, Milne T, Schreiner S, Martin M, Fuchs U, Borkhardt A, et al. Hoxa9 and Meis1 are key targets for MLL-ENL-mediated cellular immortalization. Mol Cell Biol. 2004;24:617–28.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Milne TA, Martin ME, Brock HW, Slany RK, Hess JL. Leukemogenic MLL fusion proteins bind across a broad region of the Hox a9 locus, promoting transcription and multiple histone modifications. Cancer Res. 2005;65:11367–75.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Vooijs M, Jonkers J, Berns A. A highly efficient ligand-regulated Cre recombinase mouse line shows that LoxP recombination is position dependent. EMBO Rep. 2001;2:292–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Venkatesh S, Workman JL. Histone exchange, chromatin structure and the regulation of transcription. Nat Rev Mol Cell Biol. 2015;16:178–89.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Weber C, Ramachandran S, Henikoff S. Nucleosomes are context-specific, H2A.Z-Modulated barriers to RNA polymerase. Mol Cell. 2014;53:819–30.

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Hu G, Cui K, Northrup D, Liu C, Wang C, Tang Q, et al. H2A.Z facilitates access of active and repressive complexes to chromatin in embryonic stem cell self-renewal and differentiation. Cell Stem Cell. 2013;12:180–92.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Latorre I, Chesney MA, Garrigues JM, Stempor P, Appert A, Francesconi M, et al. The DREAM complex promotes gene body H2A. Z for target repression. Genes Dev. 2013;29:495–500.

    Article  CAS  Google Scholar 

  15. 15.

    Talbert PB, Henikoff S. Histone variants–ancient wrap artists of the epigenome. Nat Rev Mol Cell Biol. 2010;11:264–75.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Creyghton MP, Markoulaki S, Levine SS, Hanna J, Lodato MA, Sha K, et al. H2AZ is enriched at polycomb complex target genes in ES cells and is necessary for lineage commitment. Cell. 2008;135:649–61.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Sevilla A, Binda O. Post-translational modifications of the histone variant h2az. Stem Cell Res. 2014;12:289–95.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Ku M, Jaffe JD, Koche RP, Rheinbay E, Endoh M, Koseki H, et al. H2A.Z landscapes and dual modifications in pluripotent and multipotent stem cells underlie complex genome regulatory functions. Genome Biol. 2012;13:R85.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Cai Y, Jin J, Tomomori-Sato C, Sato S, Sorokina I, Parmely TJ, et al. Identification of new subunits of the multiprotein mammalian TRRAP/TIP60-containing histone acetyltransferase complex. J Biol Chem. 2003;278:42733–6.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Cai Y, Jin J, Florens L, Swanson SK, Kusch T, Li B, et al. The mammalian YL1 protein is a shared subunit of the TRRAP/TIP60 histone acetyltransferase and SRCAP complexes. J Biol Chem. 2005;280:13665–70.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Ikura T, Ogryzko VV, Grigoriev M, Groisman R, Wang J, Horikoshi M, et al. Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis. Cell. 2000;102:463–73.

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Sun Y, Jiang X, Price BD. Tip60: connecting chromatin to DNA damage signaling. Cell Cycle. 2010;9:930–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Fazzio TG, Huff JT, Panning B. An RNAi screen of chromatin proteins identifies Tip60-p400 as a regulator of embryonic stem cell identity. Cell. 2008;134:162–74.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Jeong KW, Kim K, Situ AJ, Ulmer TS, An W, Stallcup MR. Recognition of enhancer element–specific histone methylation by TIP60 in transcriptional activation. Nat Struct Mol Biol. 2011;18:1358–65.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Mehta M, Braberg H, Wang S, Lozsa A, Shales M, Solache A, et al. Individual lysine acetylations on the N terminus of Saccharomyces cerevisiae H2A.Z are highly but not differentially regulated. J Biol Chem. 2010;285:39855–65.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Kusch T, Mei A, Nguyen C. Histone H3 lysine 4 trimethylation regulates cotranscriptional H2A variant exchange by Tip60 complexes to maximize gene expression. Proc Natl Acad Sci USA. 2014;111:4850–5.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Bönisch C, Schneider K, Pünzeler S, Wiedemann SM, Bielmeier C, Bocola M, et al. H2A.Z.2.2 is an alternatively spliced histone H2A.Z variant that causes severe nucleosome destabilization. Nucleic Acids Res. 2012;40:5951–64.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  28. 28.

    Kim J, Woo AJ, Chu J, Snow JW, Fujiwara Y, Kim CG, et al. A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs. Cell. 2010;143:313–24.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Gao C, Bourke E, Scobie M, Famme MA, Koolmeister T, Helleday T, et al. Rational design and validation of a Tip60 histone acetyltransferase inhibitor. Sci Rep. 2014;4:5372.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Shi J, Wang E, Milazzo JP, Wang Z, Kinney JB, Vakoc CR. Discovery of cancer drug targets by CRISPR-Cas9 screening of protein domains. Nat Biotechnol. 2015;33:1–10.

    Article  CAS  Google Scholar 

  31. 31.

    Sun Y, Sun J, Lungchukiet P, Quarni W, Yang S, Zhang X, et al. Fe65 suppresses breast cancer cell migration and invasion through Tip60 mediated cortactin acetylation. Sci Rep. 2015;5:11529.

    PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Coffey K, Blackburn TJ, Cook S, Golding BT, Griffin RJ, Hardcastle IR et al. Characterisation of a Tip60 specific inhibitor, NU9056, in prostate cancer. PLoS One. 2012;7: https://doi.org/10.1371/journal.pone.0045539.

  33. 33.

    Morita S, Kojima T, Kitamura T. Plat-E: an efficient and stable system for transient packaging of retroviruses. Gene Ther. 2000;7:1063–6.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Gévry N, Ho MC, Laflamme L, Livingston DM, Gaudreau L. p21 transcription is regulated by differential localization of histone H2A.Z. Genes Dev. 2007;21:1869–81.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. 35.

    Pradhan SK, Su T, Yen L, Jacquet K, Huang C, Cote J, et al. EP400 deposits H3. 3 into promoters and enhancers during gene activation. Mol Cell. 2016;61:27–38.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Okada Y, Feng Q, Lin Y, Jiang Q, Li Y, Coffield VM, et al. hDOT1L links histone methylation to leukemogenesis. Cell. 2005;121:167–78.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Deshpande AJ, Deshpande A, Sinha AU, Chen L, Chang J, Cihan A, et al. AF10 regulates progressive H3K79 methylation and HOX gene expression in diverse AML subtypes. Cancer Cell. 2014;26:896–908.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Garcia-Cuellar M-P, Buttner C, Bartenhagen C, Dugas M, Slany RK. Leukemogenic MLL-ENL fusions induce alternative chromatin states to drive a functionally dichotomous group of target genes. Cell Rep. 2016;15:310–22.

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Wang Q, Wu G, Mi S, He F, Wu J, Dong J, et al. MLL fusion proteins preferentially regulate a subset of wild-type MLL target genes in the leukemic genome. Blood. 2018;117:6895–906.

    Article  CAS  Google Scholar 

  40. 40.

    Daigle SR, Olhava EJ, Therkelsen CA, Majer CR, Sneeringer CJ, Song J, et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell. 2011;20:53–65.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Harris WJ, Huang X, Lynch JT, Spencer GJ, Hitchin JR, Li Y, et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell. 2012;21:473–87.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Muntean AG, Tan J, Sitwala K, Huang Y, Bronstein J, Connelly JA, et al. The PAF complex synergizes with MLL fusion proteins at HOX loci to promote leukemogenesis. Cancer Cell. 2010;17:609–21.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Cheung N, Fung TK, Zeisig BB, Holmes K, Rane JK, Mowen KA, et al. Targeting aberrant epigenetic networks mediated article targeting aberrant epigenetic networks mediated by PRMT1 and KDM4C in acute myeloid leukemia. Cancer Cell. 2016;29:32–48.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Numata A, Kwok HS, Zhou QL, Li J, Tirado-Magallanes R, Angarica VE, et al. Lysine acetyltransferase Tip60 is required for hematopoietic stem cell maintenance. Blood. 2020;136:1735–47.

    PubMed  Article  Google Scholar 

  45. 45.

    Xiao Y, Nagai Y, Deng G, Ohtani T, Zhu Z, Zhou Z, et al. Dynamic interactions between TIP60 and p300 regulate FOXP3 function through a structural switch defined by a single lysine on TIP60. Cell Rep. 2014;7:1471–80.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Rathert P, Roth M, Neumann T, Muerdter F, Roe JS, Muhar M, et al. Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. Nature. 2015;525:543–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Cui K, Zang C, Roh TY, Schones DE, Childs RW, Peng W, et al. Chromatin signatures in multipotent human hematopoietic stem cells indicate the fate of bivalent genes during differentiation. Cell Stem Cell. 2009;4:80–93.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Valdes-Mora F, Song JZ, Statham AL, Strbenac D, Robinson MD, Nair SS, et al. Acetylation of H2A.Z is a key epigenetic modification associated with gene deregulation and epigenetic remodeling in cancer. Genome Res. 2012;22:307–21.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Yukawa M, Akiyama T, Franke V, Mise N, Isagawa T, Suzuki Y et al. Genome-wide analysis of the chromatin composition of histone H2A and H3 variants in mouse embryonic stem cells. PLoS One. 2014;9; https://doi.org/10.1371/journal.pone.0092689.

  50. 50.

    Latrick CM, Marek M, Ouararhni K, Papin C, Stoll I, Ignatyeva M, et al. Molecular basis and specificity of H2A.Z–H2B recognition and deposition by the histone chaperone YL1. Nat Struct Mol Biol. 2016;23:309–16.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Liang X, Shan S, Pan L, Zhao J, Ranjan A, Wang F, et al. Structural basis of H2A.Z recognition by SRCAP chromatin-remodeling subunit YL1. Nat Struct Mol Biol. 2016;23:317–23.

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Obri A, Ouararhni K, Papin C, Diebold M-L, Padmanabhan K, Marek M, et al. ANP32E is a histone chaperone that removes H2A.Z from chromatin. Nature. 2014;505:648–53.

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Giaimo BD, Ferrante F, Vallejo DM, Hein K, Gutierrez-Perez I, Nist A, et al. Histone variant H2A.Z deposition and acetylation directs the canonical Notch signaling response. Nucleic Acids Res. 2018;46:8197–215.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by the Project for Cancer Research and Therapeutic Evolution (P-CREATE).

Author information

Affiliations

Authors

Contributions

KY, MS, SF, and YA conducted the experiments; KY and IK designed the experiments and wrote the paper.

Corresponding author

Correspondence to Issay Kitabayashi.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yamagata, K., Shino, M., Aikawa, Y. et al. Tip60 activates Hoxa9 and Meis1 expression through acetylation of H2A.Z, promoting MLL-AF10 and MLL-ENL acute myeloid leukemia. Leukemia (2021). https://doi.org/10.1038/s41375-021-01244-y

Download citation

Search

Quick links