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 to the Editor
  • Published:

Delineating MEIS1 cis-regulatory elements active in hematopoietic cells

Leukemia volume 28, pages 433–436 (2014)Cite this article

Subjects

MEIS1 (Myeloid ecotropic viral integration site 1) is a homeodomain transcription factor that cooperates with Hox family proteins in both normal and leukemic hematopoiesis.1 MEIS1 is highly expressed in hematopoietic stem cells (HSCs), and its level decreases during differentiation but with a relatively higher expression in the megakaryocytic lineage.2, 3 MEIS1 expression is often elevated in leukemia,4 and it is one of the leukemic stem cell (LSC)-related signature genes whose higher expression is correlated with worse prognosis.5 Previous work, including our own, has shown that MEIS1 acts as an important driver for leukemogenesis.1 Elevated expression of MEIS1 with concurrent high expression of HOX can induce rapid-onset AML in murine models.6 Decreased MEIS1 expression via short hairpin RNA-mediated knockdown has been shown to significantly reduce LSC potential.7, 8 Together, these findings point to the importance of tightly regulated expression of MEIS1 for normal hematopoiesis and reveal how its deregulated expression can be a major factor in leukemogenesis.

A major challenge, however, to understanding the regulation of MEIS1 is the large genomic region it spans (around 140 kb in both mouse and human with 98% non-coding region), where many potential cis-regulatory elements could function together to regulate its expression. Our previous and recent studies have provided some insights into the nature of the MEIS1 promoter region with an essential role in the regulation of MEIS1 expression9 (Supplementary Figure 1). Two recent studies have further identified the presence of multiple additional cis-regulatory elements within the MEIS1 locus through analysis of evolutionarily conserved regions from zebrafish to human.10, 11 Although such evolutionary-based approaches have helped to identify some MEIS1 cis-regulatory elements, including several regions that could be potentially involved in hematopoiesis, it leaves open the possibility of missing important regulatory regions that are not so highly conserved from fish to human.

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

Relevant articles

Open Access articles citing this article.

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

References

  1. Argiropoulos B, Yung E, Humphries RK . Unraveling the crucial roles of Meis1 in leukemogenesis and normal hematopoiesis. Genes Dev 2007; 21: 2845–2849.

    Article  CAS  Google Scholar 

  2. Pineault N, Helgason CD, Lawrence HJ, Humphries RK . Differential expression of Hox, Meis1, and Pbx1 genes in primitive cells throughout murine hematopoietic ontogeny. Exp Hematol 2002; 30: 49–57.

    Article  CAS  Google Scholar 

  3. Watkins NA, Gusnanto A, de Bono B, De S, Miranda-Saavedra D, Hardie DL et al. A HaemAtlas: characterizing gene expression in differentiated human blood cells. Blood 2009; 113: e1–e9.

    Article  CAS  Google Scholar 

  4. Thorsteinsdottir U, Kroon E, Jerome L, Blasi F, Sauvageau G . Defining roles for HOX and MEIS1 genes in induction of acute myeloid leukemia. Mol Cell Biol 2001; 21: 224–234.

    Article  CAS  Google Scholar 

  5. Eppert K, Takenaka K, Lechman ER, Waldron L, Nilsson B, van Galen P et al. Stem cell gene expression programs influence clinical outcome in human leukemia. Nat Med 2011; 17: 1086–1093.

    Article  CAS  Google Scholar 

  6. Pineault N, Abramovich C, Ohta H, Humphries RK . Differential and common leukemogenic potentials of multiple NUP98-Hox fusion proteins alone or with Meis1. Mol Cell Biol 2004; 24: 1907–1917.

    Article  CAS  Google Scholar 

  7. Wong P, Iwasaki M, Somervaille TC, So CW, Cleary ML . Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential. Genes Dev 2007; 21: 2762–2774.

    Article  CAS  Google Scholar 

  8. Kumar AR, Sarver AL, Wu B, Kersey JH . Meis1 maintains stemness signature in MLL-AF9 leukemia. Blood 2010; 115: 3642–3643.

    Article  CAS  Google Scholar 

  9. Xiang P, Lo C, Argiropoulos B, Lai CB, Rouhi A, Imren S et al. Identification of E74-like factor 1 (ELF1) as a transcriptional regulator of the Hox cofactor MEIS1. Exp Hematol 2010; 38: 798–798, 808 e1-2.

    Article  CAS  Google Scholar 

  10. Royo JL, Bessa J, Hidalgo C, Fernandez-Minan A, Tena JJ, Roncero Y et al. Identification and analysis of conserved cis-regulatory regions of the MEIS1 gene. PloS One 2012; 7: e33617.

    Article  CAS  Google Scholar 

  11. Wang QF, Li YJ, Dong JF, Li B, Kaberlein JJ, Zhang L et al. Regulation of MEIS1 by distal enhancer elements in acute leukemia. Leukemia, e-pub ahead of print 15 October 2013; doi:10.1038/leu.2013.260.

    Article  CAS  Google Scholar 

  12. Ernst J, Kellis M . Discovery and characterization of chromatin states for systematic annotation of the human genome. Nat Biotechnol 2010; 28: 817–825.

    Article  CAS  Google Scholar 

  13. Kulaeva OI, Nizovtseva EV, Polikanov YS, Ulianov SV, Studitsky VM . Distant activation of transcription: mechanisms of enhancer action. Mol Cell Biol 2012; 32: 4892–4897.

    Article  CAS  Google Scholar 

  14. Phillips JE, Corces VG . CTCF: master weaver of the genome. Cell 2009; 137: 1194–1211.

    Article  Google Scholar 

  15. Sarry JE, Murphy K, Perry R, Sanchez PV, Secreto A, Keefer C et al. Human acute myelogenous leukemia stem cells are rare and heterogeneous when assayed in NOD/SCID/IL2Rgammac-deficient mice. J Clin Investig 2011; 121: 384–395.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We sincerely thank other lab members in Dr Keith Humphries’ laboratory for helpful discussion. This work is supported by the Terry Fox Foundation Program Project Grant (TFF-122869) and CIHR (RMF-92093).

Author information

Authors and Affiliations

  1. Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada

    P Xiang, W Wei, C Lo, P Rosten, J Hou, P A Hoodless & K R Humphries

  2. University of British Columbia, Medical Genetics, Vancouver, British Columbia, Canada

    P A Hoodless

  3. BC Cancer Agency, Canada’s Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada

    M Bilenky & M Hirst

  4. School of Cancer Sciences, College of Medical and Dental Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham, UK

    C Bonifer

  5. School of Immunity and Infection, College of Medical and Dental Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham, UK

    P N Cockerill

  6. Department of Haematology, Cambridge Institute for Medical Research and Wellcome Trust and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK

    A Kirkpatrick & B Gottgens

Authors
  1. P Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C Lo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P Rosten
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P A Hoodless
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Bilenky
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C Bonifer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P N Cockerill
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A Kirkpatrick
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. B Gottgens
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. M Hirst
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. K R Humphries
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K R Humphries.

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

Cite this article

Xiang, P., Wei, W., Lo, C. et al. Delineating MEIS1 cis-regulatory elements active in hematopoietic cells. Leukemia 28, 433–436 (2014). https://doi.org/10.1038/leu.2013.287

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2013.287

This article is cited by

Search

Advanced search

Quick links