Original Article | Published:

Stem cell biology

Rictor has a pivotal role in maintaining quiescence as well as stemness of leukemia stem cells in MLL-driven leukemia

Leukemia volume 31, pages 414422 (2017) | Download Citation

Abstract

Little is known about the roles of Rictor/mTORC2 in the leukemogenesis of acute myeloid leukemia. Here, we demonstrated that Rictor is essential for the maintenance of mixed lineage leukemia (MLL)-driven leukemia by preventing leukemia stem cells (LSCs) from exhaustion. Rictor depletion led to a reactive activation of mTORC1 signaling by facilitating the assembly of mTORC1. Hyperactivated mTORC1 signaling in turn drove LSCs into cycling, compromised the quiescence of LSCs and eventually exhausted their capacity to generate leukemia. At the same time, loss of Rictor had led to a reactive activation of FoxO3a in leukemia cells, which acts as negative feedback to restrain greater over-reactivation of mTORC1 activity and paradoxically protects leukemia cells from exhaustion. Simultaneous depletion of Rictor and FoxO3a enabled rapid exhaustion of MLL LSCs and a quick eradication of MLL leukemia. As such, our present findings highlighted a pivotal regulatory axis of Rictor-FoxO3a in maintaining quiescence and the stemness of LSCs.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

Gene Expression Omnibus

References

  1. 1.

    . Looking ahead in cancer stem cell research. Nat Biotechnol 2009; 27: 44–46.

  2. 2.

    , , , , , et al. beta-Catenin mediates the establishment and drug resistance of MLL leukemic stem cells. Cancer Cell 2010; 18: 606–618.

  3. 3.

    , , , , , et al. The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science 2010; 327: 1650–1653.

  4. 4.

    , , , , , et al. Clonal evolution enhances leukemia-propagating cell frequency in T cell acute lymphoblastic leukemia through Akt/mTORC1 pathway activation. Cancer Cell 2014; 25: 366–378.

  5. 5.

    , , , , , et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 2006; 441: 475–482.

  6. 6.

    , , , , , et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 2006; 441: 518–522.

  7. 7.

    . mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 2006; 6: 729–734.

  8. 8.

    , , , , , et al. mTOR complex 1 plays critical roles in hematopoiesis and Pten-loss-evoked leukemogenesis. Cell Stem Cell 2012; 11: 429–439.

  9. 9.

    , , , , , et al. Loss of mTOR complex 1 induces developmental blockage in early T-lymphopoiesis and eradicates T-cell acute lymphoblastic leukemia cells. Proc Natl Acad Sci USA 2014; 111: 3805–3810.

  10. 10.

    , , , , , et al. Mammalian target of rapamycin (mTOR) inhibition activates phosphatidylinositol 3-kinase/Akt by up-regulating insulin-like growth factor-1 receptor signaling in acute myeloid leukemia: rationale for therapeutic inhibition of both pathways. Blood 2008; 111: 379–382.

  11. 11.

    , . The pharmacology of mTOR inhibition. Sci Signal 2009; 2: pe24.

  12. 12.

    , , , , , et al. mTORC1 is essential for leukemia propagation but not stem cell self-renewal. J Clin Invest 2012; 122: 2114–2129.

  13. 13.

    , , , , , . Temporal changes in PTEN and mTORC2 regulation of hematopoietic stem cell self-renewal and leukemia suppression. Cell Stem Cell 2012; 11: 415–428.

  14. 14.

    , , , , , et al. Vital roles of mTOR complex 2 in Notch-driven thymocyte differentiation and leukemia. J Exp Med 2012; 209: 713–728.

  15. 15.

    , . Therapeutic targeting of MLL. Blood 2009; 113:6061–6068.

  16. 16.

    , , , , , et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 2011; 20: 53–65.

  17. 17.

    , , , , , et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 2011; 478: 529–533.

  18. 18.

    , , , , , et al. Azacitidine fails to eradicate leukemic stem/progenitor cell populations in patients with acute myeloid leukemia and myelodysplasia. Leukemia 2013; 27: 1028–1036.

  19. 19.

    , , , , . Survival and hospitalization among patients with acute myeloid leukemia treated with azacitidine or decitabine in a large managed care population: a real-world, retrospective, claims-based, comparative analysis. Exp Hematol Oncol 2014; 3: 10.

  20. 20.

    , , , , . Rictor/mTORC2 is essential for maintaining a balance between beta-cell proliferation and cell size. Diabetes 2011; 60: 827–837.

  21. 21.

    , , , , , et al. Rictor is required for early B cell development in bone marrow. PLoS One 2014; 9: e103970.

  22. 22.

    , . Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer Cell 2006; 10: 257–268.

  23. 23.

    , , , , , et al. Rictor/mammalian target of rapamycin 2 regulates the development of Notch1 induced murine T-cell acute lymphoblastic leukemia via forkhead box O3. Exp Hematol 2014; 42: 1031–1040, e1031-e1034.

  24. 24.

    , , , . Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307: 1098–1101.

  25. 25.

    , , , , , et al. Identification of functional cooperative mutations of SETD2 in human acute leukemia. Nat Genet 2014; 46: 287–293.

  26. 26.

    , . mTOR signaling in growth control and disease. Cell 2012; 149: 274–293.

  27. 27.

    , , , , , et al. FoxOs inhibit mTORC1 and activate Akt by inducing the expression of Sestrin3 and Rictor. Dev Cell 2010; 18: 592–604.

  28. 28.

    , , , , , et al. mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell 2009; 15: 148–159.

  29. 29.

    , , , , , et al. TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J Exp Med 2008; 205: 2397–2408.

  30. 30.

    , , , , , et al. PML targeting eradicates quiescent leukaemia-initiating cells. Nature 2008; 453: 1072–1078.

  31. 31.

    , , , , , . Ablation of Fbxw7 eliminates leukemia-initiating cells by preventing quiescence. Cancer Cell 2013; 23: 347–361.

  32. 32.

    , , , . mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling. Mol Cell Biol 2010; 30: 908–921.

  33. 33.

    , , , , , et al. AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias. Cell 2011; 146: 697–708.

  34. 34.

    , , , , , et al. Dual PI3K/mTOR inhibition shows antileukemic activity in MLL-rearranged acute myeloid leukemia. Leukemia 2015; 29: 828–838.

  35. 35.

    , , , , , et al. Requirement for Rictor in homeostasis and function of mature B lymphoid cells. Blood 2013; 122: 2369–2379.

  36. 36.

    , , , , , et al. RICTOR amplification defines a novel subset of patients with lung cancer who may benefit from treatment with mTORC1/2 inhibitors. Cancer Discov 2015; 5: 1262–1270.

Download references

Acknowledgements

We thank Jiang J (Department of Developmental Biology, University of Texas Southwestern Medical Center at Dallas) for discussions and suggestions and Dr MA Magnuson from Vanderbilt University for providing the Rictorfl/fl mice. This work was supported in part by the ‘863’ Program (2012AA02A507) and ‘973’ Program (2012CB966604) of the China Ministry of Science and Technology; National Natural Science Funds of China (81025011, 81230052, 81090414, 81572565, 81500137).

Author contributions

Conception and design: Y Fang, Y Yang, JF Zhou. Development of methodology: Y Fang, Y Yang, CL Hua, M Zhou. Acquisition of data: Y Fang, Y Yang, CL Hua, SM Xu, HD Guo, N Wang, H Cheng. Analysis and interpretation of data (for example, statistical analysis, flow cytometry interpretation): Y Fang, Y Yang, CL Hua, SM Xu, XJ Zhao, L Huang, F Yu. Writing, review and/or revision of the manuscript: Y Fang, Y Yang, JF Zhou. Administrative, technical or material support: L Meng, T Cheng, Michael L Wang. Study supervision: WP Yuan, D Ma, JF Zhou.

Author information

Author notes

    • Y Fang
    • , Y Yang
    • , C Hua
    •  & S Xu

    These authors contributed equally to this work

Affiliations

  1. Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    • Y Fang
    • , Y Yang
    • , S Xu
    • , M Zhou
    • , N Wang
    • , X Zhao
    • , L Huang
    • , F Yu
    • , L Meng
    •  & J Zhou
  2. Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    • Y Fang
    • , Y Yang
    • , S Xu
    • , M Zhou
    • , N Wang
    • , L Huang
    • , F Yu
    • , L Meng
    • , D Ma
    •  & J Zhou
  3. State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China

    • C Hua
    • , H Guo
    • , H Cheng
    • , T Cheng
    •  & W Yuan
  4. Department of Lymphoma/ Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • M L Wang

Authors

  1. Search for Y Fang in:

  2. Search for Y Yang in:

  3. Search for C Hua in:

  4. Search for S Xu in:

  5. Search for M Zhou in:

  6. Search for H Guo in:

  7. Search for N Wang in:

  8. Search for X Zhao in:

  9. Search for L Huang in:

  10. Search for F Yu in:

  11. Search for H Cheng in:

  12. Search for M L Wang in:

  13. Search for L Meng in:

  14. Search for T Cheng in:

  15. Search for W Yuan in:

  16. Search for D Ma in:

  17. Search for J Zhou in:

Competing interests

The authors declare no conflict of interest.

Corresponding authors

Correspondence to W Yuan or D Ma or J Zhou.

Supplementary information

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/leu.2016.223

Supplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu)

Further reading