Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2016

Open Access 01-12-2016 | Research

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

Authors: 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

Published in: Journal of Hematology & Oncology | Issue 1/2016

Login to get access

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 Rheb1 Δ/Δ AML cells. The mTOR activator 3BDO partially rescued mTORC1 signaling and inhibited apoptosis in Rheb1 Δ/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.
Appendix
Available only for authorised users
Literature
1.
Burnett AK. Acute myeloid leukemia: treatment of adults under 60 years. Rev Clin Exp Hematol. 2002;6(1):26–45. discussion 86-27.CrossRefPubMed
2.
Ma S, Shi Y, Pang Y, Dong F, Cheng H, Hao S, Xu J, Zhu X, Yuan W, Cheng T, Zheng G. Notch1-induced T cell leukemia can be potentiated by microenvironmental cues in the spleen. J Hematol Oncol. 2014;7:71.CrossRefPubMedPubMedCentral
3.
Erb U, Megaptche AP, Gu X, Buchler MW, Zoller M. CD44 standard and CD44v10 isoform expression on leukemia cells distinctly influences niche embedding of hematopoietic stem cells. J Hematol Oncol. 2014;7:29.CrossRefPubMedPubMedCentral
4.
Somervaille TCP, Cleary ML. Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer Cell. 2006;10(4):257–68.CrossRefPubMed
5.
6.
Wang Y, Krivtsov AV, Sinha AU, North TE, Goessling W, Feng Z, Zon LI, Armstrong SA. The Wnt/-catenin pathway is required for the development of leukemia stem cells in AML. Science. 2010;327(5973):1650–3.CrossRefPubMedPubMedCentral
7.
Ma XM, Blenis J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol. 2009;10(5):307–18.CrossRefPubMed
8.
Steelman LS, Abrams SL, Whelan J, Bertrand FE, Ludwig DE, Bäsecke J, Libra M, Stivala F, Milella M, Tafuri A, Lunghi P, Bonati A, Martelli AM, McCubrey JA. Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia. Leukemia. 2008;22(4):686–707.CrossRefPubMed
9.
10.
Chen C, Liu Y, Liu R, Ikenoue T, Guan KL, Zheng P. TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J Exp Med. 2008;205(10):2397–408.CrossRefPubMedPubMedCentral
11.
Yilmaz ÖH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H, Morrison SJ. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature. 2006;441(7092):475–82.CrossRefPubMed
12.
Hoshii T, Tadokoro Y, Naka K, Ooshio T, Muraguchi T, Sugiyama N, Soga T, Araki K, Yamamura K-I, Hirao A. mTORC1 is essential for leukemia propagation but not stem cell self-renewal. J Clin Invest. 2012;122(6):2114–29.CrossRefPubMedPubMedCentral
13.
Recher C, Beyne-Rauzy O, Demur C, Chicanne G, Dos Santos C, Mas VM, Benzaquen D, Laurent G, Huguet F, Payrastre B. Antileukemic activity of rapamycin in acute myeloid leukemia. Blood. 2005;105(6):2527–34.CrossRefPubMed
14.
Chiarini F, Evangelisti C, McCubrey JA, Martelli AM. Current treatment strategies for inhibiting mTOR in cancer. Trends Pharmacol Sci. 2015;36(2):124–35.CrossRefPubMed
15.
Patel PH. Drosophila Rheb GTPase is required for cell cycle progression and cell growth. J Cell Sci. 2003;116(17):3601–10.CrossRefPubMed
16.
Saucedo LJ, Gao X, Chiarelli DA, Li L, Pan D, Edgar BA. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat Cell Biol. 2003;5(6):566–71.CrossRefPubMed
17.
Goorden SM, Hoogeveen-Westerveld M, Cheng C, van Woerden GM, Mozaffari M, Post L, Duckers HJ, Nellist M, Elgersma Y. Rheb is essential for murine development. Mol Cell Biol. 2011;31(8):1672–8.CrossRefPubMedPubMedCentral
18.
Zou J, Zhou L, Du X-X, Ji Y, Xu J, Tian J, Jiang W, Zou Y, Yu S, Gan L, Luo M, Yang Q, Cui Y, Yang W, Xia X, Chen M, Zhao X, Shen Y, Chen PY, Worley PF, Xiao B. Rheb1 is required for mTORC1 and myelination in postnatal brain development. Dev Cell. 2011;20(1):97–108.CrossRefPubMedPubMedCentral
19.
20.
Zhang Y, Gao X, Saucedo LJ, Ru B, Edgar BA, Pan D. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol. 2003;5(6):578–81.CrossRefPubMed
21.
22.
23.
Zheng H, Liu A, Liu B, Li M, Yu H, Luo X. Ras homologue enriched in brain is a critical target of farnesyltransferase inhibitors in non-small cell lung cancer cells. Cancer Lett. 2010;297(1):117–25.CrossRefPubMed
24.
25.
Platt FM, Hurst CD, Taylor CF, Gregory WM, Harnden P, Knowles MA. Spectrum of phosphatidylinositol 3-kinase pathway gene alterations in bladder cancer. Clin Cancer Res. 2009;15(19):6008–17.CrossRefPubMed
26.
Kobayashi T, Shimizu Y, Terada N, Yamasaki T, Nakamura E, Toda Y, Nishiyama H, Kamoto T, Ogawa O, Inoue T. Regulation of androgen receptor transactivity and mTOR-S6 kinase pathway by Rheb in prostate cancer cell proliferation. Prostate. 2010;70(8):866–74.PubMed
27.
Eom M, Han A, Yi SY, Shin JJ, Cui Y, Park KH. RHEB expression in fibroadenomas of the breast. Pathol Int. 2008;58(4):226–32.CrossRefPubMed
28.
Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA, Golub TR, Meyerson M, Gabriel SB, Lander ES, Getz G. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature. 2014;505(7484):495–501.CrossRefPubMedPubMedCentral
29.
Mavrakis KJ, Zhu H, Silva RL, Mills JR, Teruya-Feldstein J, Lowe SW, Tam W, Pelletier J, Wendel HG. Tumorigenic activity and therapeutic inhibition of Rheb GTPase. Genes Dev. 2008;22(16):2178–88.CrossRefPubMedPubMedCentral
30.
Hebestreit K, Grottrup S, Emden D, Veerkamp J, Ruckert C, Klein HU, Muller-Tidow C, Dugas M. Leukemia Gene Atlas—a public platform for integrative exploration of genome-wide molecular data. PLoS One. 2012;7(6):e39148.CrossRefPubMedPubMedCentral
31.
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, Cerami E, Sander C, Schultz N. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269):l1.CrossRef
32.
Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y, Faber J, Levine JE, Wang J, Hahn WC, Gilliland DG, Golub TR, Armstrong SA. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature. 2006;442(7104):818–22.CrossRefPubMed
33.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):15545–50.CrossRefPubMedPubMedCentral
34.
Collins C, Wang J, Miao H, Bronstein J, Nawer H, Xu T, Figueroa M, Muntean AG, Hess JL. C/EBPalpha is an essential collaborator in Hoxa9/Meis1-mediated leukemogenesis. Proc Natl Acad Sci U S A. 2014;111(27):9899–904.CrossRefPubMedPubMedCentral
35.
Faber J, Krivtsov AV, Stubbs MC, Wright R, Davis TN, van den Heuvel-Eibrink M, Zwaan CM, Kung AL, Armstrong SA. HOXA9 is required for survival in human MLL-rearranged acute leukemias. Blood. 2009;113(11):2375–85.CrossRefPubMedPubMedCentral
36.
37.
Zhang Y, Lima CF, Rodrigues LR. Anticancer effects of lactoferrin: underlying mechanisms and future trends in cancer therapy. Nutr Rev. 2014;72(12):763–73.CrossRefPubMed
38.
Lopez-Otin C, Palavalli LH, Samuels Y. Protective roles of matrix metalloproteinases: from mouse models to human cancer. Cell Cycle. 2009;8(22):3657–62.CrossRefPubMedPubMedCentral
39.
Johnson JJ, Chen W, Hudson W, Yao Q, Taylor M, Rabbitts TH, Kersey JH. Prenatal and postnatal myeloid cells demonstrate stepwise progression in the pathogenesis of MLL fusion gene leukemia. Blood. 2003;101(8):3229–35.CrossRefPubMed
40.
41.
Sherr CJ, Roberts JM. Living with or without cyclins and cyclin-dependent kinases. Genes Dev. 2004;18(22):2699–711.CrossRefPubMed
42.
Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999;13(12):1501–12.CrossRefPubMed
43.
Horne MC, Donaldson KL, Goolsby GL, Tran D, Mulheisen M, Hell JW, Wahl AF. Cyclin G2 is up-regulated during growth inhibition and B cell antigen receptor-mediated cell cycle arrest. J Biol Chem. 1997;272(19):12650–61.CrossRefPubMed
44.
Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 2008;9(1):47–59.CrossRefPubMed
45.
46.
Ge D, Han L, Huang S, Peng N, Wang P, Jiang Z, Zhao J, Su L, Zhang S, Zhang Y, Kung H, Zhao B, Miao J. Identification of a novel MTOR activator and discovery of a competing endogenous RNA regulating autophagy in vascular endothelial cells. Autophagy. 2014;10(6):957–71.CrossRefPubMedPubMedCentral
47.
Garami A, Zwartkruis FJ, Nobukuni T, Joaquin M, Roccio M, Stocker H, Kozma SC, Hafen E, Bos JL, Thomas G. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell. 2003;11(6):1457–66.CrossRefPubMed
48.
Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 2006;441(7092):424–30.CrossRefPubMed
49.
Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev. 1999;13(22):2905–27.CrossRefPubMed
50.
Min YH, Eom JI, Cheong JW, Maeng HO, Kim JY, Jeung HK, Lee ST, Lee MH, Hahn JS, Ko YW. Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukemia: its significance as a prognostic variable. Leukemia. 2003;17(5):995–7.CrossRefPubMed
51.
Kornblau SM, Tibes R, Qiu YH, Chen W, Kantarjian HM, Andreeff M, Coombes KR, Mills GB. Functional proteomic profiling of AML predicts response and survival. Blood. 2009;113(1):154–64.CrossRefPubMedPubMedCentral
52.
53.
Hope KJ, Jin L, Dick JE. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol. 2004;5(7):738–43.CrossRefPubMed
54.
Schulenburg A, Blatt K, Cerny-Reiterer S, Sadovnik I, Herrmann H, Marian B, Grunt TW, Zielinski CC, Valent P. Cancer stem cells in basic science and in translational oncology: can we translate into clinical application? J Hematol Oncol. 2015;8:16.CrossRefPubMedPubMedCentral
55.
Akala OO, Clarke MF. Hematopoietic stem cell self-renewal. Curr Opin Genet Dev. 2006;16(5):496–501.CrossRefPubMed
56.
Nishioka C, Ikezoe T, Yang J, Yokoyama A. Inhibition of MEK/ERK signaling induces apoptosis of acute myelogenous leukemia cells via inhibition of eukaryotic initiation factor 4E-binding protein 1 and down-regulation of Mcl-1. Apoptosis. 2010;15(7):795–804.CrossRefPubMed
57.
58.
Lacher MD, Pincheira R, Zhu Z, Camoretti-Mercado B, Matli M, Warren RS, Castro AF. Rheb activates AMPK and reduces p27Kip1 levels in Tsc2-null cells via mTORC1-independent mechanisms: implications for cell proliferation and tumorigenesis. Oncogene. 2010;29(50):6543–56.CrossRefPubMed
59.
Campos T, Ziehe J, Palma M, Escobar D, Tapia JC, Pincheira R, Castro AF. Rheb promotes cancer cell survival through p27Kip1-dependent activation of autophagy. Mol Carcinog. 2015. doi:10.​1002/​mc.​22272.PubMed
Metadata
Title
Rheb1 promotes tumor progression through mTORC1 in MLL-AF9-initiated murine acute myeloid leukemia
Authors
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
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2016
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-016-0264-3

Other articles of this Issue 1/2016

Journal of Hematology & Oncology 1/2016 Go to the issue

Review

Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor

Research

H2S protects against fatal myelosuppression by promoting the generation of megakaryocytes/platelets

Review

Targeting histone methylation for cancer therapy: enzymes, inhibitors, biological activity and perspectives

Research

The expression profile and clinic significance of the SIX family in non-small cell lung cancer

Letter to the Editor

Systematic analysis of overall survival and interactions between tumor mutations and drug treatment

Research highlight

Chasing the precursor of functional hematopoietic stem cells at the single cell levels in mouse embryos
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits