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:

Gaq signaling is required for the maintenance of MLL-AF9-induced acute myeloid leukemia

Leukemia volume 30, pages 1745–1748 (2016)Cite this article

Subjects

Self-renewal and differentiation block are two key features of leukemic stem cells (LSCs) in mixed-lineage leukemia (MLL)-rearranged acute myeloid leukemia (AML), which can originate from either hematopoietic stem cells (HSCs) or granulocyte macrophage progenitors (GMPs). We have previously demonstrated that β-catenin is essential for the establishment of MLL LSCs, where MLL-AF9 activates β-catenin, one role of which is to confer self-renewal capacity to GMPs, necessary for malignant transformation.1 The effect of β-catenin appears to be largely context-dependent and driven by its upstream components that fine-tune the signal to modulate different functional programs downstream of β-catenin.2 The targeting of critical upstream components could therefore serve as a potential strategy to effectively block β-catenin signaling. However, our understanding of upstream signaling events leading to β-catenin activation in leukemia still remains poor.

G proteins and G protein-coupled receptors have been implicated in playing crucial roles in multiple cancers, where specific members of this family influence self-renewal and tumorigenesis, largely through activation of β-catenin signaling.2 The G protein subunit Gaq has recently been identified as a direct target of MLL-AF4,3 and Dot1l-mediated H3K79 methylation marks are enriched at the Gaq locus in MLL-AF9 LSCs,4 indicating a role for Gaq in MLL leukemia.

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

References

  1. Wang Y, Krivtsov AV, Sinha AU, North TE, Goessling W, Feng Z et al. The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science 2010; 327: 1650–1653.

    Article  CAS  Google Scholar 

  2. Dietrich PA, Yang C, Leung HH, Lynch JR, Gonzales E, Liu B et al. GPR84 sustains aberrant beta-catenin signaling in leukemic stem cells for maintenance of MLL leukemogenesis. Blood 2014; 124: 3284–3294.

    Article  CAS  Google Scholar 

  3. Guenther MG, Lawton LN, Rozovskaia T, Frampton GM, Levine SS, Volkert TL et al. Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia. Genes Dev 2008; 22: 3403–3408.

    Article  CAS  Google Scholar 

  4. 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.

    Article  CAS  Google Scholar 

  5. Mukai H, Munekata E, Higashijima T . G protein antagonists. A novel hydrophobic peptide competes with receptor for G protein binding. J Biol Chem 1992; 267: 16237–16243.

    CAS  PubMed  Google Scholar 

  6. Man CH, Fung TK, Wan H, Cher CY, Fan A, Ng N et al. Suppression of SOX7 by DNA methylation and its tumor suppressor function in acute myeloid leukemia. Blood 2015; 125: 3928–3936.

    Article  CAS  Google Scholar 

  7. Tran H, Brunet A, Grenier JM, Datta SR, Fornace AJ Jr, DiStefano PS et al. DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science 2002; 296: 530–534.

    Article  CAS  Google Scholar 

  8. Li N, Ragheb K, Lawler G, Sturgis J, Rajwa B, Melendez JA et al. Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. J Biol Chem 2003; 278: 8516–8525.

    Article  CAS  Google Scholar 

  9. Yeung J, Esposito MT, Gandillet A, Zeisig BB, Griessinger E, Bonnet D et al. beta-Catenin mediates the establishment and drug resistance of MLL leukemic stem cells. Cancer Cell 2010; 18: 606–618.

    Article  CAS  Google Scholar 

  10. Lagadinou ED, Sach A, Callahan K, Rossi RM, Neering SJ, Minhajuddin M et al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell 2013; 12: 329–341.

    Article  CAS  Google Scholar 

  11. Lehwald N, Tao GZ, Jang KY, Papandreou I, Liu B, Liu B et al. beta-Catenin regulates hepatic mitochondrial function and energy balance in mice. Gastroenterology 2012; 143: 754–764.

    Article  CAS  Google Scholar 

  12. Lento W, Ito T, Zhao C, Harris JR, Huang W, Jiang C et al. Loss of beta-catenin triggers oxidative stress and impairs hematopoietic regeneration. Genes Dev 2014; 28: 995–1004.

    Article  CAS  Google Scholar 

  13. Stubbs MC, Kim YM, Krivtsov AV, Wright RD, Feng Z, Agarwal J et al. MLL-AF9 and FLT3 cooperation in acute myelogenous leukemia: development of a model for rapid therapeutic assessment. Leukemia 2008; 22: 66–77.

    Article  CAS  Google Scholar 

  14. Perugini M, Kok CH, Brown AL, Wilkinson CR, Salerno DG, Young SM et al. Repression of Gadd45alpha by activated FLT3 and GM-CSF receptor mutants contributes to growth, survival and blocked differentiation. Leukemia 2009; 23: 729–738.

    Article  CAS  Google Scholar 

  15. Heximer SP, Watson N, Linder ME, Blumer KJ, Hepler JR . RGS2/G0S8 is a selective inhibitor of Gqalpha function. Proc Natl Acad Sci USA 1997; 94: 14389–14393.

    Article  CAS  Google Scholar 

  16. Schwable J, Choudhary C, Thiede C, Tickenbrock L, Sargin B, Steur C et al. RGS2 is an important target gene of Flt3-ITD mutations in AML and functions in myeloid differentiation and leukemic transformation. Blood 2005; 105: 2107–2114.

    Article  Google Scholar 

Download references

Acknowledgements

JW is an Australian Research Council Future Fellow (FT120100612) and was supported by the National Health and Medical Research Council (APP1066897). This work was supported by the grant from the Cancer Council New South Wales (RG15-11) to JW. Children's Cancer Institute, Australia is affiliated with the University of New South Wales and Sydney Children’s Hospitals Network, Australia.

Author contributions

JL designed and performed the experiments and analyzed the data. HY, FV, EG and TF performed the experiments. DC designed and performed human AML experiments. BL performed microarray data analysis and provided statistical support. AB prepared the human AML material. MH, MN, CS and TL provided reagents and reviewed the paper. IL reviewed and provided the human AML material. RD designed human AML experiments and edited the paper. JW designed the experiments and wrote the paper.

Author information

Authors and Affiliations

  1. Cancer and Stem Cell Biology Group, Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia

    J R Lynch, H Yi, F Voli, E Gonzales-Aloy & J Y Wang

  2. Acute Leukemia Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia

    D A Casolari, A Brown, I D Lewis & R J D’Andrea

  3. Department of Haematology, SA Pathology and Royal Adelaide Hospital, Adelaide, South Australia, Australia

    D A Casolari, I D Lewis & R J D’Andrea

  4. Department of Haematological Medicine, Leukaemia and Stem Cell Biology Group, King's College London, Denmark Hill, London, UK

    T K Fung & C W E So

  5. Kids Cancer Alliance, Translational Cancer Research Centre for Kids, Cancer Institute New South Wales, Sydney, NSW, Australia

    B Liu

  6. Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, South Australia, Australia

    A Brown

  7. Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia

    T Liu, M Haber & M D Norris

  8. Centre for Childhood Cancer Research, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia

    T Liu, M D Norris & J Y Wang

Authors
  1. J R Lynch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D A Casolari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F Voli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E Gonzales-Aloy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T K Fung
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. T Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M Haber
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M D Norris
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. I D Lewis
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. C W E So
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. R J D’Andrea
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. J Y Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Y Wang.

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

Lynch, J., Yi, H., Casolari, D. et al. Gaq signaling is required for the maintenance of MLL-AF9-induced acute myeloid leukemia. Leukemia 30, 1745–1748 (2016). https://doi.org/10.1038/leu.2016.24

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2016.24

This article is cited by

Search

Advanced search

Quick links