nach oben

International Journal of Hematology

Erschienen in:

20.01.2016 | Progress in Hematology

mTORC signaling in hematopoiesis

verfasst von: Xiaomin Wang, Yajing Chu, Weili Wang, Weiping Yuan

Erschienen in: International Journal of Hematology | Ausgabe 5/2016

Einloggen, um Zugang zu erhalten

Abstract

mTOR is a serine/threonine (Ser/Thr) protein kinase that responds to multiple signals, including growth factors, amino acids, energy status, stress, and oxygen, regulates cell survival, cell growth, the cell cycle, and cell metabolism, and maintains homeostasis [1]. Increased or decreased mTORC1 activity can alter HSC function and cause hematological disorders [2, 3]. Therefore, a comprehensive knowledge of mTOR is critical to understanding how HSCs function and maintain homeostasis in the hematopoietic system. In this review, we summarize recent advances in the understanding of the mTOR signaling pathway and its roles in hematopoiesis and leukemia. We also discuss pharmacological approaches to manipulate mTOR activity.

Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274–93.CrossRefPubMedPubMedCentral

Hoshii T, et al. mTORC1 is essential for leukemia propagation but not stem cell self-renewal. J Clin Invest. 2012;122(6):2114–29.CrossRefPubMedPubMedCentral

Kentsis A, Look AT. Distinct and dynamic requirements for mTOR signaling in hematopoiesis and leukemogenesis. Cell Stem Cell. 2012;11(3):281–2.CrossRefPubMed

Cafferkey R, et al. Dominant missense mutations in a novel yeast protein related to mammalian phosphatidylinositol 3-kinase and VPS34 abrogate rapamycin cytotoxicity. Mol Cell Biol. 1993;13(10):6012–23.CrossRefPubMedPubMedCentral

Kunz J, Hall MN. Cyclosporin A, FK506 and rapamycin: more than just immunosuppression. Trends Biochem Sci. 1993;18(9):334–8.CrossRefPubMed

Brown EJ, et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature. 1994;369(6483):756–8.CrossRefPubMed

Sabatini DM, et al. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell. 1994;78(1):35–43.CrossRefPubMed

Sabers CJ, et al. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem. 1995;270(2):815–22.CrossRefPubMed

Lee CH, et al. Constitutive mTOR activation in TSC mutants sensitizes cells to energy starvation and genomic damage via p53. EMBO J. 2007;26(23):4812–23.CrossRefPubMedPubMedCentral

10.

Kim DH, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell. 2002;110(2):163–75.CrossRefPubMed

11.

Jacinto E, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004;6(11):1122–8.CrossRefPubMed

12.

Peterson TR, et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell. 2009;137(5):873–86.CrossRefPubMedPubMedCentral

13.

Kaizuka T, et al. Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. J Biol Chem. 2010;285(26):20109–16.CrossRefPubMedPubMedCentral

14.

Hara K, et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell. 2002;110(2):177–89.CrossRefPubMed

15.

Jacinto E, et al. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell. 2006;127(1):125–37.CrossRefPubMed

16.

Pearce LR, et al. Identification of protor as a novel rictor-binding component of mTOR complex-2. Biochem J. 2007;405(3):513–22.CrossRefPubMedPubMedCentral

17.

Sancak Y, et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell. 2007;25(6):903–15.CrossRefPubMed

18.

Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med. 2006;355(13):1345–56.CrossRefPubMed

19.

Roux PP, et al. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc Natl Acad Sci. 2004;101(37):13489–94.CrossRefPubMedPubMedCentral

20.

Ma L, et al. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell. 2005;121(2):179–93.CrossRefPubMed

21.

Aspuria PJ, Tamanoi F. The Rheb family of GTP-binding proteins. Cell Signal. 2004;16(10):1105–12.CrossRefPubMed

22.

Inoki K, et al. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 2003;17(15):1829–34.CrossRefPubMedPubMedCentral

23.

Inoki K, et al. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell. 2006;126(5):955–68.CrossRefPubMed

24.

Blommaart EF, et al. Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. J Biol Chem. 1995;270(5):2320–6.CrossRefPubMed

25.

Cook SJ, Morley SJ. Nutrient-responsive mTOR signalling grows on Sterile ground. Biochem J. 2007;403(1):e1–3.CrossRefPubMedPubMedCentral

26.

Sancak Y, et al. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell. 2010;141(2):290–303.CrossRefPubMedPubMedCentral

27.

Nojima H, et al. The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif. J Biol Chem. 2003;278(18):15461–4.CrossRefPubMed

28.

Schalm SS, et al. TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr Biol. 2003;13(10):797–806.CrossRefPubMed

29.

Ma XM, Blenis J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol. 2009;10(5):307–18.CrossRefPubMed

30.

Brugarolas JB, et al. TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell. 2003;4(2):147–58.CrossRefPubMed

31.

Settembre C, et al. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 2012;31(5):1095–108.CrossRefPubMedPubMedCentral

32.

Moore SF, Hunter RW, Hers I. mTORC2 protein complex-mediated Akt (protein kinase B) serine 473 phosphorylation is not required for Akt1 activity in human platelets (corrected). J Biol Chem. 2011;286(28):24553–60.CrossRefPubMedPubMedCentral

33.

Sarbassov DD, et al. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307(5712):1098–101.CrossRefPubMed

34.

Guertin DA, et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell. 2006;11(6):859–71.CrossRefPubMed

35.

Garcia-Martinez JM, Alessi DR. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J. 2008;416(3):375–85.CrossRefPubMed

36.

Gangloff YG, et al. Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development. Mol Cell Biol. 2004;24(21):9508–16.CrossRefPubMedPubMedCentral

37.

Murakami M, et al. mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol Cell Biol. 2004;24(15):6710–8.CrossRefPubMedPubMedCentral

38.

Shiota C, et al. Multiallelic disruption of the rictor gene in mice reveals that mTOR complex 2 is essential for fetal growth and viability. Dev Cell. 2006;11(4):583–9.CrossRefPubMed

39.

Guo F, et al. Mouse gene targeting reveals an essential role of mTOR in hematopoietic stem cell engraftment and hematopoiesis. Haematologica. 2013;98(9):1353–8.CrossRefPubMedPubMedCentral

40.

Chen C, et al. The axis of mTOR-mitochondria-ROS and stemness of the hematopoietic stem cells. Cell Cycle. 2009;8(8):1158–60.CrossRefPubMed

41.

Chen C, 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(10):2397–408.CrossRefPubMedPubMedCentral

42.

Gan B, et al. mTORC1-dependent and -independent regulation of stem cell renewal, differentiation, and mobilization. Proc Natl Acad Sci. 2008;105(49):19384–9.CrossRefPubMedPubMedCentral

43.

Chen C, et al. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal. 2009;2(98):ra75.CrossRefPubMedPubMedCentral

44.

Kalaitzidis D, et al. mTOR complex 1 plays critical roles in hematopoiesis and Pten-loss-evoked leukemogenesis. Cell Stem Cell. 2012;11(3):429–39.CrossRefPubMedPubMedCentral

45.

Magee JA, et al. Temporal changes in PTEN and mTORC2 regulation of hematopoietic stem cell self-renewal and leukemia suppression. Cell Stem Cell. 2012;11(3):415–28.CrossRefPubMedPubMedCentral

46.

Zhang Y, et al. Rictor is required for early B cell development in bone marrow. PLoS One. 2014;9(8):e103970.CrossRefPubMedPubMedCentral

47.

Hoshii T, 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. 2014;111(10):3805–10.CrossRefPubMedPubMedCentral

48.

Chi H. Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol. 2012;12(5):325–38.PubMedPubMedCentral

49.

Lee K, et al. Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity. 2010;32(6):743–53.CrossRefPubMedPubMedCentral

50.

Delgoffe GM, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity. 2009;30(6):832–44.CrossRefPubMedPubMedCentral

51.

Lee K et al. Vital roles of mTOR complex 2 in Notch-driven thymocyte differentiation and leukemia. J Exp Med. 2012.

52.

Tang F, et al. A critical role for Rictor in T lymphopoiesis. J Immunol. 2012;189(4):1850–7.CrossRefPubMedPubMedCentral

53.

Araki K, et al. mTOR regulates memory CD8 T-cell differentiation. Nature. 2009;460(7251):108–12.CrossRefPubMedPubMedCentral

54.

Pollizzi KN, et al. mTORC1 and mTORC2 selectively regulate CD8(+) T cell differentiation. J Clin Invest. 2015;125(5):2090–108.CrossRefPubMedPubMedCentral

55.

Zeng H, et al. mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. Nature. 2013;499(7459):485–90.CrossRefPubMedPubMedCentral

56.

Lee K, et al. Requirement for Rictor in homeostasis and function of mature B lymphoid cells. Blood. 2013;122(14):2369–79.CrossRefPubMedPubMedCentral

57.

Knight ZA, et al. A critical role for mTORC1 in erythropoiesis and anemia. Elife. 2014;3:e01913.CrossRefPubMedPubMedCentral

58.

Huang J, et al. Maintenance of hematopoietic stem cells through regulation of Wnt and mTOR pathways. Nat Med. 2012;18(12):1778–85.CrossRefPubMedPubMedCentral

59.

Huang J, et al. Pivotal role for glycogen synthase kinase-3 in hematopoietic stem cell homeostasis in mice. J Clin Invest. 2009;119(12):3519–29.PubMedPubMedCentral

60.

Jang YY, Sharkis SJ. A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood. 2007;110(8):3056–63.CrossRefPubMedPubMedCentral

61.

Liu W, et al. PTEN mutation: many birds with one stone in tumorigenesis. Anticancer Res. 2008;28(6A):3613–9.PubMed

62.

Lee JY, et al. mTOR activation induces tumor suppressors that inhibit leukemogenesis and deplete hematopoietic stem cells after Pten deletion. Cell Stem Cell. 2010;7(5):593–605.CrossRefPubMedPubMedCentral

63.

Martelli AM, et al. The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients. Oncotarget. 2010;1(2):89–103.CrossRefPubMedPubMedCentral

64.

Mullally A, Ebert BL. NF1 inactivation revs up Ras in adult acute myelogenous leukemia. Clin Cancer Res. 2010;16(16):4074–6.CrossRefPubMed

65.

Kornblau SM, et al. Functional proteomic profiling of AML predicts response and survival. Blood. 2009;113(1):154–64.CrossRefPubMedPubMedCentral

66.

Wang Y, et al. The Wnt/-catenin pathway is required for the development of leukemia stem cells in AML. Science. 2010;327(5973):16501653.CrossRef

67.

Weng AP, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004;306(5694):269–71.CrossRefPubMed

68.

Chan SM, et al. Notch signals positively regulate activity of the mTOR pathway in T-cell acute lymphoblastic leukemia. Blood. 2007;110(1):278–86.CrossRefPubMedPubMedCentral

69.

Hales EC, Taub JW, Matherly LH. New insights into Notch1 regulation of the PI3K–AKT–mTOR1 signaling axis: targeted therapy of gamma-secretase inhibitor resistant T-cell acute lymphoblastic leukemia. Cell Signal. 2014;26(1):149–61.CrossRefPubMed

70.

Cullion K, et al. Targeting the Notch1 and mTOR pathways in a mouse T-ALL model. Blood. 2009;113(24):6172–81.CrossRefPubMedPubMedCentral

71.

Hua C, 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(12):1031.CrossRefPubMed

72.

Yilmaz OH, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature. 2006;441(7092):475–82.CrossRefPubMed

73.

Zhang J, et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature. 2006;441(7092):518–22.CrossRefPubMed

74.

Sykes SM, et al. AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias. Cell. 2011;146(5):697–708.CrossRefPubMed

75.

Nemes K, et al. Mammalian target of rapamycin (mTOR) activity dependent phospho-protein expression in childhood acute lymphoblastic leukemia (ALL). PLoS One. 2013;8(4):e59335.CrossRefPubMedPubMedCentral

76.

Beagle BR, et al. mTOR kinase inhibitors synergize with histone deacetylase inhibitors to kill B-cell acute lymphoblastic leukemia cells. Oncotarget. 2015;6(4):2088–100.CrossRefPubMedPubMedCentral

77.

Brown VI, et al. Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling. Proc Natl Acad Sci. 2003;100(25):15113–8.CrossRefPubMedPubMedCentral

78.

Tasian SK, et al. Aberrant STAT5 and PI3K/mTOR pathway signaling occurs in human CRLF2-rearranged B-precursor acute lymphoblastic leukemia. Blood. 2012;120(4):833–42.CrossRefPubMedPubMedCentral

79.

Maude SL, et al. Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia. Blood. 2012;120(17):3510–8.CrossRefPubMedPubMedCentral

80.

Wall M, et al. The mTORC1 inhibitor everolimus prevents and treats Emu-Myc lymphoma by restoring oncogene-induced senescence. Cancer Discov. 2013;3(1):82–95.CrossRefPubMedPubMedCentral

81.

Ravitz MJ, et al. c-myc repression of TSC2 contributes to control of translation initiation and Myc-induced transformation. Cancer Res. 2007;67(23):11209–17.CrossRefPubMedPubMedCentral

82.

Sarbassov DD, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell. 2006;22(2):159–68.CrossRefPubMed

83.

Hipp S, et al. Inhibition of the mammalian target of rapamycin and the induction of cell cycle arrest in mantle cell lymphoma cells. Haematologica. 2005;90(10):1433–4.PubMed

84.

Witzig TE, et al. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol. 2005;23(23):5347–56.CrossRefPubMed

85.

Witzig TE, Kaufmann SH. Inhibition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in hematologic malignancies. Curr Treat Options Oncol. 2006;7(4):285–94.CrossRefPubMed

86.

Recher C, et al. Antileukemic activity of rapamycin in acute myeloid leukemia. Blood. 2005;105(6):2527–34.CrossRefPubMed

87.

Fransecky L, Mochmann LH, Baldus CD. Outlook on PI3K/AKT/mTOR inhibition in acute leukemia. Mol Cell Ther. 2015;3:2.CrossRefPubMedPubMedCentral

88.

Nowak P, et al. Discovery of potent and selective inhibitors of the mammalian target of rapamycin (mTOR) kinase. J Med Chem. 2009;52(22):7081–9.CrossRefPubMed

89.

Feldman ME, et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 2009;7(2):e38.CrossRefPubMed

90.

Thoreen CC, et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem. 2009;284(12):8023–32.CrossRefPubMedPubMedCentral

91.

Willems L, et al. The dual mTORC1 and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia. Leukemia. 2012;26(6):1195–202.CrossRefPubMed

92.

Janes MR, et al. Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nat Med. 2010;16(2):205–13.CrossRefPubMedPubMedCentral

93.

Evangelisti C, et al. Targeted inhibition of mTORC1 and mTORC2 by active-site mTOR inhibitors has cytotoxic effects in T-cell acute lymphoblastic leukemia. Leukemia. 2011;25(5):781–91.CrossRefPubMed

94.

Zeng Z, et al. Targeting of mTORC1/2 by the mTOR kinase inhibitor PP242 induces apoptosis in AML cells under conditions mimicking the bone marrow microenvironment. Blood. 2012;120(13):2679–89.CrossRefPubMedPubMedCentral

95.

Simioni C, et al. Activity of the novel mTOR inhibitor Torin-2 in B-precursor acute lymphoblastic leukemia and its therapeutic potential to prevent Akt reactivation. Oncotarget. 2014;5(20):10034–47.CrossRefPubMedPubMedCentral

96.

Vilar E, Perez-Garcia J, Tabernero J. Pushing the envelope in the mTOR pathway: the second generation of inhibitors. Mol Cancer Ther. 2011;10(3):395–403.CrossRefPubMedPubMedCentral

97.

Chang X, et al. Sin1 regulates Treg-cell development but is not required for T-cell growth and proliferation. Eur J Immunol. 2012;42(6):1639–47.CrossRefPubMedPubMedCentral

Titel: mTORC signaling in hematopoiesis
verfasst von: Xiaomin Wang
Yajing Chu
Weili Wang
Weiping Yuan
Publikationsdatum: 20.01.2016
Verlag: Springer Japan
Erschienen in: International Journal of Hematology / Ausgabe 5/2016
Print ISSN: 0925-5710
Elektronische ISSN: 1865-3774
DOI: https://doi.org/10.1007/s12185-016-1944-z

Neu im Fachgebiet Onkologie

25.04.2024 | Nierenkarzinom | Nachrichten

Springer Medizin

mTORC signaling in hematopoiesis

Abstract

Neu im Fachgebiet Onkologie

Adjuvante Immuntherapie verlängert Leben bei RCC

Alectinib verbessert krankheitsfreies Überleben bei ALK-positivem NSCLC

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Update Onkologie

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 5/2016

Multiple myeloma with Russell bodies and needle-shaped crystalline inclusions

Antigen expression on a putative leukemic stem cell population and AML blast

“Imatinib-induced gastric antral vascular ectasia” in a reporting system of the Japanese Adverse Drug Event Report database

The combination effects of bendamustine with antimetabolites against childhood acute lymphoblastic leukemia cells

JAK2V617F allele burden in patients with myeloproliferative neoplasms carrying Trisomy 9, and its relationship with clinical phenotypes

Comparison of myocardial T1 and T2 values in 3 T with T2* in 1.5 T in patients with iron overload and controls

Neu im Fachgebiet Onkologie

Adjuvante Immuntherapie verlängert Leben bei RCC

Alectinib verbessert krankheitsfreies Überleben bei ALK-positivem NSCLC

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Update Onkologie