Rheb1 promotes tumor progression through mTORC1 in MLL-AF9- initiated murine acute myeloid leukemia

Yanan Gao, Juan Gao, Minghao Li, Yawei Zheng, Yajie Wang, Hongyan Zhang, Weili Wang, Yajing Chu, Xiaomin Wang, Mingjiang Xu, Tao Cheng, Zhenyu Ju, Weiping Yuan

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Background: The constitutive hyper-activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways has frequently been associated with acute myeloid leukemia (AML). While many inhibitors targeting these pathways have been developed, the anti-leukemic effect was not as robust as expected. As part of the molecular link between PI3K/Akt and mTOR kinase, the role of Rheb1 in AML remains unexplored. Our study aims to explore the role of Rheb1 in AML and estimate whether Rheb1 could be a potential target of AML treatment. Methods: The expressions of Rheb1 and other indicated genes were analyzed using real-time PCR. AML mouse model was established by retrovirus transduction. Leukemia cell properties and related signaling pathways were dissected by in vitro and in vivo studies. The transcriptional changes were analyzed via gene chip analysis. Molecular reagents including mTOR inhibitor and mTOR activator were used to evaluate the function of related signaling pathway in the mouse model. Results: We observed that Rheb1 is overexpressed in AML patients and the change of Rheb1 level in AML patients is associated with their median survival. Using a Rheb1-deficient MLL-AF9 murine AML model, we revealed that Rheb1 deletion prolonged the survival of AML mice by weakening LSC function. In addition, Rheb1 deletion arrested cell cycle progression and enhanced apoptosis of AML cells. Furthermore, while Rheb1 deletion reduced mTORC1 activity in AML cells, additional rapamycin treatment further decreased mTORC1 activity and increased the apoptosis of Rheb1Δ/Δ AML cells. The mTOR activator 3BDO partially rescued mTORC1 signaling and inhibited apoptosis in Rheb1Δ/Δ AML cells. Conclusions: Our data suggest that Rheb1 promotes AML progression through mTORC1 signaling pathway and combinational drug treatments targeting Rheb1 and mTOR might have a better therapeutic effect on leukemia.

Original languageEnglish (US)
Article number36
JournalJournal of Hematology and Oncology
Volume9
Issue number1
DOIs
StatePublished - Jan 1 2016

Keywords

  • 3BDO
  • Leukemia
  • MLL-AF9
  • Rapamycin
  • Rheb1
  • mTORC1

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Oncology
  • Cancer Research

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  • Cite this

    Gao, Y., Gao, J., Li, M., Zheng, Y., Wang, Y., Zhang, H., Wang, W., Chu, Y., Wang, X., Xu, M., Cheng, T., Ju, Z., & Yuan, W. (2016). Rheb1 promotes tumor progression through mTORC1 in MLL-AF9- initiated murine acute myeloid leukemia. Journal of Hematology and Oncology, 9(1), [36]. https://doi.org/10.1186/s13045-016-0264-3