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.

  • Original Article
  • Published:

Transcriptional control and signal transduction, cell cycle

C-terminal BRE overexpression in 11q23-rearranged and t(8;16) acute myeloid leukemia is caused by intragenic transcription initiation

Leukemia volume 32, pages 828–836 (2018)Cite this article

Subjects

Abstract

Overexpression of the BRE (brain and reproductive organ-expressed) gene defines a distinct pediatric and adult acute myeloid leukemia (AML) subgroup. Here we identify a promoter enriched for active chromatin marks in BRE intron 4 causing strong biallelic expression of a previously unknown C-terminal BRE transcript. This transcript starts with BRE intron 4 sequences spliced to exon 5 and downstream sequences, and if translated might code for an N terminally truncated BRE protein. Remarkably, the new BRE transcript was highly expressed in over 50% of 11q23/KMT2A (lysine methyl transferase 2A)-rearranged and t(8;16)/KAT6A-CREBBP cases, while it was virtually absent from other AML subsets and normal tissues. In gene reporter assays, the leukemia-specific fusion protein KMT2A-MLLT3 transactivated the intragenic BRE promoter. Further epigenome analyses revealed 97 additional intragenic promoter marks frequently bound by KMT2A in AML with C-terminal BRE expression. The corresponding genes may be part of a context-dependent KMT2A-MLLT3-driven oncogenic program, because they were higher expressed in this AML subtype compared with other groups. C-terminal BRE might be an important contributor to this program because in a case with relapsed AML, we observed an ins(11;2) fusing CHORDC1 to BRE at the region where intragenic transcription starts in KMT2A-rearranged and KAT6A-CREBBP AML.

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
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Hinai AA, Valk PJ . Review: aberrant EVI1 expression in acute myeloid leukaemia. Br J Haematol 2016; 172: 870–878.

    Article  CAS  PubMed  Google Scholar 

  2. Groschel S, Sanders MA, Hoogenboezem R, de Wit E, Bouwman BA, Erpelinck C et al. A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia. Cell 2014; 157: 369–381.

    Article  CAS  PubMed  Google Scholar 

  3. Yamazaki H, Suzuki M, Otsuki A, Shimizu R, Bresnick EH, Engel JD et al. A remote GATA2 hematopoietic enhancer drives leukemogenesis in inv(3)(q21;q26) by activating EVI1 expression. Cancer Cell 2014; 25: 415–427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Senyuk V, Sinha KK, Li D, Rinaldi CR, Yanamandra S, Nucifora G . Repression of RUNX1 activity by EVI1: a new role of EVI1 in leukemogenesis. Cancer Res 2007; 67: 5658–5666.

    Article  CAS  PubMed  Google Scholar 

  5. Laricchia-Robbio L, Fazzina R, Li D, Rinaldi CR, Sinha KK, Chakraborty S et al. Point mutations in two EVI1 Zn fingers abolish EVI1-GATA1 interaction and allow erythroid differentiation of murine bone marrow cells. Mol Cell Biol 2006; 26: 7658–7666.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Laricchia-Robbio L, Premanand K, Rinaldi CR, Nucifora G . EVI1 Impairs myelopoiesis by deregulation of PU.1 function. Cancer Res 2009; 69: 1633–1642.

    Article  CAS  PubMed  Google Scholar 

  7. Swansbury GJ, Slater R, Bain BJ, Moorman AV, Secker-Walker LM . Hematological malignancies with t(9;11)(p21-22;q23)—a laboratory and clinical study of 125 cases. European 11q23 Workshop participants. Leukemia 1998; 12: 792–800.

    Article  CAS  PubMed  Google Scholar 

  8. Rubnitz JE, Raimondi SC, Tong X, Srivastava DK, Razzouk BI, Shurtleff SA et al. Favorable impact of the t(9;11) in childhood acute myeloid leukemia. J Clin Oncol 2002; 20: 2302–2309.

    Article  CAS  PubMed  Google Scholar 

  9. Arai S, Yoshimi A, Shimabe M, Ichikawa M, Nakagawa M, Imai Y et al. Evi-1 is a transcriptional target of mixed-lineage leukemia oncoproteins in hematopoietic stem cells. Blood 2011; 117: 6304–6314.

    Article  CAS  PubMed  Google Scholar 

  10. Noordermeer SM, Monteferrario D, Sanders MA, Bullinger L, Jansen JH, van der Reijden BA . Improved classification of MLL-AF9-positive acute myeloid leukemia patients based on BRE and EVI1 expression. Blood 2012; 119: 4335–4337.

    Article  CAS  PubMed  Google Scholar 

  11. Balgobind BV, Zwaan CM, Reinhardt D, Arentsen-Peters TJ, Hollink IH, de Haas V et al. High BRE expression in pediatric MLL-rearranged AML is associated with favorable outcome. Leukemia 2010; 24: 2048–2055.

    Article  CAS  PubMed  Google Scholar 

  12. Noordermeer SM, Sanders MA, Gilissen C, Tonnissen E, van der Heijden A, Dohner K et al. High BRE expression predicts favorable outcome in adult acute myeloid leukemia, in particular among MLL-AF9-positive patients. Blood 2011; 118: 5613–5621.

    Article  CAS  PubMed  Google Scholar 

  13. Chui YL, Ma CH, Li W, Xu Z, Yao Y, Lin FK et al. Anti-apoptotic protein BRE/BRCC45 attenuates apoptosis through maintaining the expression of caspase inhibitor XIAP in mouse Lewis lung carcinoma D122 cells. Apoptosis 2014; 19: 829–840.

    Article  CAS  PubMed  Google Scholar 

  14. Dong Y, Hakimi MA, Chen X, Kumaraswamy E, Cooch NS, Godwin AK et al. Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair. Mol Cell 2003; 12: 1087–1099.

    Article  CAS  PubMed  Google Scholar 

  15. Chan JY, Li L, Miao J, Cai DQ, Lee KK, Chui YL . Differential expression of a novel gene BRE (TNFRSF1A modulator/BRCC45) in response to stress and biological signals. Mol Biol Rep 2010; 37: 363–368.

    Article  CAS  PubMed  Google Scholar 

  16. Shi W, Tang MK, Yao Y, Tang C, Chui YL, Lee KK . BRE plays an essential role in preventing replicative and DNA damage-induced premature senescence. Scientific Rep 2016; 6: 23506.

    Article  CAS  Google Scholar 

  17. Feng L, Huang J, Chen J . MERIT40 facilitates BRCA1 localization and DNA damage repair. Genes Dev 2009; 23: 719–728.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Patterson-Fortin J, Shao G, Bretscher H, Messick TE, Greenberg RA . Differential regulation of JAMM domain deubiquitinating enzyme activity within the RAP80 complex. J Biol Chem 2010; 285: 30971–30981.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kyrieleis OJ, McIntosh PB, Webb SR, Calder LJ, Lloyd J, Patel NA et al. Three-dimensional architecture of the human BRCA1-A histone deubiquitinase core complex. Cell Rep 2016; 17: 3099–3106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yan K, Li L, Wang X, Hong R, Zhang Y, Yang H et al. The deubiquitinating enzyme complex BRISC is required for proper mitotic spindle assembly in mammalian cells. J Cell Biol 2015; 210: 209–224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Valk PJ, Verhaak RG, Beijen MA, Erpelinck CA, Barjesteh van Waalwijk van Doorn-Khosrovani S, Boer JM et al. Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med 2004; 350: 1617–1628.

    Article  CAS  PubMed  Google Scholar 

  22. Haferlach T, Kohlmann A, Klein HU, Ruckert C, Dugas M, Williams PM et al. AML with translocation t(8;16)(p11;p13) demonstrates unique cytomorphological, cytogenetic, molecular and prognostic features. Leukemia 2009; 23: 934–943.

    Article  CAS  PubMed  Google Scholar 

  23. Coenen EA, Zwaan CM, Reinhardt D, Harrison CJ, Haas OA, de Haas V et al. Pediatric acute myeloid leukemia with t(8;16)(p11;p13), a distinct clinical and biological entity: a collaborative study by the International-Berlin-Frankfurt-Munster AML-study group. Blood 2013; 122: 2704–2713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wouters BJ, Lowenberg B, Erpelinck-Verschueren CA, van Putten WL, Valk PJ, Delwel R . Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome. Blood 2009; 113: 3088–3091.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Prange KH, Mandoli A, Kuznetsova T, Wang SY, Sotoca AM, Marneth AE et al. MLL-AF9 and MLL-AF4 oncofusion proteins bind a distinct enhancer repertoire and target the RUNX1 program in 11q23 acute myeloid leukemia. Oncogene 2017; 36: 3346–3356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Di Savino A, Panuzzo C, Rocca S, Familiari U, Piazza R, Crivellaro S et al. Morgana acts as an oncosuppressor in chronic myeloid leukemia. Blood 2015; 125: 2245–2253.

    Article  CAS  PubMed  Google Scholar 

  27. Castilla LH, Perrat P, Martinez NJ, Landrette SF, Keys R, Oikemus S et al. Identification of genes that synergize with Cbfb-MYH11 in the pathogenesis of acute myeloid leukemia. Proc Natl Acad Sci USA 2004; 101: 4924–4929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Landrette SF, Kuo YH, Hensen K, Barjesteh van Waalwijk van Doorn-Khosrovani S, Perrat PN, Van de Ven WJ et al. Plag1 and Plagl2 are oncogenes that induce acute myeloid leukemia in cooperation with Cbfb-MYH11. Blood 2005; 105: 2900–2907.

    Article  CAS  PubMed  Google Scholar 

  29. Slany RK . The molecular mechanics of mixed lineage leukemia. Oncogene 2016; 35: 5215–5223.

    Article  CAS  PubMed  Google Scholar 

  30. Marschalek R . Systematic classification of mixed-lineage leukemia fusion partners predicts additional cancer pathways. Ann Lab Med 2016; 36: 85–100.

    Article  CAS  PubMed  Google Scholar 

  31. Chan EM, Chan RJ, Comer EM, Goulet RJ, Crean CD, Brown ZD et al. MOZ and MOZ-CBP cooperate with NF-kappaB to activate transcription from NF-kappaB-dependent promoters. Exp Hematol 2007; 35: 1782–1792.

    Article  CAS  PubMed  Google Scholar 

  32. Paggetti J, Largeot A, Aucagne R, Jacquel A, Lagrange B, Yang XJ et al. Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells. Oncogene 2010; 29: 5019–5031.

    Article  CAS  PubMed  Google Scholar 

  33. Katsumoto T, Yoshida N, Kitabayashi I . Roles of the histone acetyltransferase monocytic leukemia zinc finger protein in normal and malignant hematopoiesis. Cancer Sci 2008; 99: 1523–1527.

    Article  CAS  PubMed  Google Scholar 

  34. Kitabayashi I, Aikawa Y, Nguyen LA, Yokoyama A, Ohki M . Activation of AML1-mediated transcription by MOZ and inhibition by the MOZ-CBP fusion protein. EMBO J 2001; 20: 7184–7196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Roy R, Chun J, Powell SN . BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer 2011; 12: 68–78.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Zhang J, Cao M, Dong J, Li C, Xu W, Zhan Y et al. ABRO1 suppresses tumourigenesis and regulates the DNA damage response by stabilizing p53. Nat Commun 2014; 5: 5059.

    Article  CAS  PubMed  Google Scholar 

  37. Huang D, Nagata Y, Grossmann V, Radivoyevitch T, Okuno Y, Nagae G et al. BRCC3 mutations in myeloid neoplasms. Haematologica 2015; 100: 1051–1057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chan BC, Ching AK, To KF, Leung JC, Chen S LiQ et al. BRE is an antiapoptotic protein in vivo and overexpressed in human hepatocellular carcinoma. Oncogene 2008; 27: 1208–1217.

    Article  CAS  PubMed  Google Scholar 

  39. Chen HB, Pan K, Tang MK, Chui YL, Chen L, Su ZJ et al. Comparative proteomic analysis reveals differentially expressed proteins regulated by a potential tumor promoter, BRE, in human esophageal carcinoma cells. Biochem Cell Biol 2008; 86: 302–311.

    Article  CAS  PubMed  Google Scholar 

  40. Zheng S, Cherniack AD, Dewal N, Moffitt RA, Danilova L, Murray BA et al. Comprehensive pan-genomic characterization of adrenocortical carcinoma. Cancer Cell 2016; 29: 723–736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Noordermeer SM, Wennemers M, Bergevoet SM, van der Heijden A, Tonnissen E, Sweep FC et al. Expression of the BRCA1 complex member BRE predicts disease free survival in breast cancer. Breast Cancer Res Treat 2012; 135: 125–133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Dr Robert Slany for kindly sharing the pGL3-Hoxa7 promoter plasmid. This work was supported by the Radboud University Medical Center for Oncology, the Dutch Cancer Foundation (KUN 2011-4937) and the European Union’s Seventh Framework Programme (FP5/2007-2013, 282510-BLUEPRINT).

Author contributions

AEM, KHMP, BAR and JHAM coordinated research and wrote the manuscript. AEM, KHMP and SMB conducted and analyzed most experiments. KHMP, EMJM, BK, NS, MLY, JK, HGS and JHAM contributed to ChIP-seq and RNA-sequencing of KMT2A-MLLT3 samples (BLUEPRINT consortium). KHMP, NT and MAS did bioinformatic analyses. ASAAH, ECGS, JK, MAS and PJMV detected CHORDC1-BRE fusion. TCJMA-P, CMZ, HGS, MMH-E, TH, MF, JHJ, PJMV, BAR and JHM provided patient samples and funding. All authors critically revised the paper and approved the final version.

Author information

Author notes

  1. A E Marneth, K H M Prange, B A van der Reijden and J H A Martens: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands

    A E Marneth, S M Bergevoet, J H Jansen & B A van der Reijden

  2. Department of Molecular Biology, Faculty of Science, RIMLS, Radboud University, Nijmegen, The Netherlands

    K H M Prange, N Tesi, E M Janssen-Megens, B Kim, N Sharifi, J Kuster, H G Stunnenberg & J H A Martens

  3. Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands

    A S A Al Hinai, M A Sanders, E C G Stoetman & P J M Valk

  4. Max Planck Institute for Molecular Genetics, Berlin, Germany

    M L Yaspo

  5. Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands

    J Knijnenburg

  6. Pediatric Oncology/Hematology, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands

    T C J M Arentsen-Peters, C M Zwaan, M M van den Heuvel-Eibrink & M Fornerod

  7. Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands

    M M van den Heuvel-Eibrink

  8. MLL Munich Leukemia Laboratory, Munich, Germany

    T Haferlach

Authors
  1. A E Marneth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K H M Prange
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A S A Al Hinai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S M Bergevoet
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N Tesi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E M Janssen-Megens
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. N Sharifi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M L Yaspo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J Kuster
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M A Sanders
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. E C G Stoetman
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. J Knijnenburg
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. T C J M Arentsen-Peters
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. C M Zwaan
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. H G Stunnenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. M M van den Heuvel-Eibrink
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. T Haferlach
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. M Fornerod
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. J H Jansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. P J M Valk
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. B A van der Reijden
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. J H A Martens
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to B A van der Reijden or J H A Martens.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Marneth, A., Prange, K., Al Hinai, A. et al. C-terminal BRE overexpression in 11q23-rearranged and t(8;16) acute myeloid leukemia is caused by intragenic transcription initiation. Leukemia 32, 828–836 (2018). https://doi.org/10.1038/leu.2017.280

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2017.280

This article is cited by

Search

Advanced search

Quick links