MTOR complex 1 plays critical roles in hematopoiesis and pten-loss-evoked leukemogenesis

Demetrios Kalaitzidis; Stephen M. Sykes; Zhu Wang; Natalie Punt; Yuefeng Tang; Christine Ragu; Amit U. Sinha; Steven W. Lane; Amanda L. Souza; Clary B. Clish; Dimitrios Anastasiou; D. Gary Gilliland; David T. Scadden; David A. Guertin; Scott A. Armstrong

doi:10.1016/j.stem.2012.06.009

MTOR complex 1 plays critical roles in hematopoiesis and pten-loss-evoked leukemogenesis

Demetrios Kalaitzidis, Stephen M. Sykes, Zhu Wang, Natalie Punt, Yuefeng Tang, Christine Ragu, Amit U. Sinha, Steven W. Lane, Amanda L. Souza, Clary B. Clish, Dimitrios Anastasiou, D. Gary Gilliland, David T. Scadden, David A. Guertin, Scott A. Armstrong

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Abstract

The mechanistic target of rapamycin (mTOR) pathway serves as a key sensor of cellular-energetic state and functions to maintain tissue homeostasis. Hyperactivation of the mTOR pathway impairs hematopoietic stem cell (HSC) function and is associated with leukemogenesis. However, the roles of the unique mTOR complexes (mTORCs) in hematopoiesis and leukemogenesis have not been adequately elucidated. We deleted the mTORC1 component, regulatory-associated protein of mTOR (Raptor), in mouse HSCs and its loss causes a nonlethal phenotype characterized by pancytopenia, splenomegaly, and the accumulation of monocytoid cells. Furthermore, Raptor is required for HSC regeneration, and plays largely nonredundant roles with rapamycin-insensitive companion of mTOR (Rictor) in these processes. Ablation of Raptor also significantly extends survival of mice in models of leukemogenesis evoked by Pten deficiency. These data delineate critical roles for mTORC1 in hematopoietic function and leukemogenesis and inform clinical strategies based on chronic mTORC1 inhibition.

Original language	English
Pages (from-to)	429-439
Number of pages	11
Journal	Cell Stem Cell
Volume	11
Issue number	3
DOIs	https://doi.org/10.1016/j.stem.2012.06.009
State	Published - Sep 7 2012

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Kalaitzidis, D., Sykes, S. M., Wang, Z., Punt, N., Tang, Y., Ragu, C., Sinha, A. U., Lane, S. W., Souza, A. L., Clish, C. B., Anastasiou, D., Gilliland, D. G., Scadden, D. T., Guertin, D. A., & Armstrong, S. A. (2012). MTOR complex 1 plays critical roles in hematopoiesis and pten-loss-evoked leukemogenesis. Cell Stem Cell, 11(3), 429-439. https://doi.org/10.1016/j.stem.2012.06.009

@article{d2be3bb6131248df84eaf94e1ee0f058,

title = "MTOR complex 1 plays critical roles in hematopoiesis and pten-loss-evoked leukemogenesis",

abstract = "The mechanistic target of rapamycin (mTOR) pathway serves as a key sensor of cellular-energetic state and functions to maintain tissue homeostasis. Hyperactivation of the mTOR pathway impairs hematopoietic stem cell (HSC) function and is associated with leukemogenesis. However, the roles of the unique mTOR complexes (mTORCs) in hematopoiesis and leukemogenesis have not been adequately elucidated. We deleted the mTORC1 component, regulatory-associated protein of mTOR (Raptor), in mouse HSCs and its loss causes a nonlethal phenotype characterized by pancytopenia, splenomegaly, and the accumulation of monocytoid cells. Furthermore, Raptor is required for HSC regeneration, and plays largely nonredundant roles with rapamycin-insensitive companion of mTOR (Rictor) in these processes. Ablation of Raptor also significantly extends survival of mice in models of leukemogenesis evoked by Pten deficiency. These data delineate critical roles for mTORC1 in hematopoietic function and leukemogenesis and inform clinical strategies based on chronic mTORC1 inhibition.",

author = "Demetrios Kalaitzidis and Sykes, {Stephen M.} and Zhu Wang and Natalie Punt and Yuefeng Tang and Christine Ragu and Sinha, {Amit U.} and Lane, {Steven W.} and Souza, {Amanda L.} and Clish, {Clary B.} and Dimitrios Anastasiou and Gilliland, {D. Gary} and Scadden, {David T.} and Guertin, {David A.} and Armstrong, {Scott A.}",

note = "Funding Information: We wish to thank Rebekka Schneider-Kramann for assistance with pathology, Kristina M. Brumme for assistance with mouse husbandry, and Michael G. Kharas for review of the manuscript. D.K. was supported by NIDDK grant K01DK092300; C.B.C. was partially supported by the Nestle Research Center; D.G.G. is currently a full-time employee of Merck and Co. Inc.; D.T.S. was supported by NIH grants HL097794, HL097748, HL100402, and DK050234; D.A.G. was supported by NIH grant R00 CA129613 and the PEW Charitable Trust; and S.A.A. was supported by grants from the Leukemia and Lymphoma Society, The American Cancer Society, The Charles H. Hood Foundation, and NIH grants CA66996, CA105423, and DK049216. ",

year = "2012",

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doi = "10.1016/j.stem.2012.06.009",

language = "English",

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T1 - MTOR complex 1 plays critical roles in hematopoiesis and pten-loss-evoked leukemogenesis

AU - Kalaitzidis, Demetrios

AU - Sykes, Stephen M.

AU - Wang, Zhu

AU - Punt, Natalie

AU - Tang, Yuefeng

AU - Ragu, Christine

AU - Sinha, Amit U.

AU - Lane, Steven W.

AU - Souza, Amanda L.

AU - Clish, Clary B.

AU - Anastasiou, Dimitrios

AU - Gilliland, D. Gary

AU - Scadden, David T.

AU - Guertin, David A.

AU - Armstrong, Scott A.

N1 - Funding Information: We wish to thank Rebekka Schneider-Kramann for assistance with pathology, Kristina M. Brumme for assistance with mouse husbandry, and Michael G. Kharas for review of the manuscript. D.K. was supported by NIDDK grant K01DK092300; C.B.C. was partially supported by the Nestle Research Center; D.G.G. is currently a full-time employee of Merck and Co. Inc.; D.T.S. was supported by NIH grants HL097794, HL097748, HL100402, and DK050234; D.A.G. was supported by NIH grant R00 CA129613 and the PEW Charitable Trust; and S.A.A. was supported by grants from the Leukemia and Lymphoma Society, The American Cancer Society, The Charles H. Hood Foundation, and NIH grants CA66996, CA105423, and DK049216.

PY - 2012/9/7

Y1 - 2012/9/7

N2 - The mechanistic target of rapamycin (mTOR) pathway serves as a key sensor of cellular-energetic state and functions to maintain tissue homeostasis. Hyperactivation of the mTOR pathway impairs hematopoietic stem cell (HSC) function and is associated with leukemogenesis. However, the roles of the unique mTOR complexes (mTORCs) in hematopoiesis and leukemogenesis have not been adequately elucidated. We deleted the mTORC1 component, regulatory-associated protein of mTOR (Raptor), in mouse HSCs and its loss causes a nonlethal phenotype characterized by pancytopenia, splenomegaly, and the accumulation of monocytoid cells. Furthermore, Raptor is required for HSC regeneration, and plays largely nonredundant roles with rapamycin-insensitive companion of mTOR (Rictor) in these processes. Ablation of Raptor also significantly extends survival of mice in models of leukemogenesis evoked by Pten deficiency. These data delineate critical roles for mTORC1 in hematopoietic function and leukemogenesis and inform clinical strategies based on chronic mTORC1 inhibition.

AB - The mechanistic target of rapamycin (mTOR) pathway serves as a key sensor of cellular-energetic state and functions to maintain tissue homeostasis. Hyperactivation of the mTOR pathway impairs hematopoietic stem cell (HSC) function and is associated with leukemogenesis. However, the roles of the unique mTOR complexes (mTORCs) in hematopoiesis and leukemogenesis have not been adequately elucidated. We deleted the mTORC1 component, regulatory-associated protein of mTOR (Raptor), in mouse HSCs and its loss causes a nonlethal phenotype characterized by pancytopenia, splenomegaly, and the accumulation of monocytoid cells. Furthermore, Raptor is required for HSC regeneration, and plays largely nonredundant roles with rapamycin-insensitive companion of mTOR (Rictor) in these processes. Ablation of Raptor also significantly extends survival of mice in models of leukemogenesis evoked by Pten deficiency. These data delineate critical roles for mTORC1 in hematopoietic function and leukemogenesis and inform clinical strategies based on chronic mTORC1 inhibition.

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AN - SCOPUS:84866082606

SN - 1934-5909

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SP - 429

EP - 439

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 3

ER -

MTOR complex 1 plays critical roles in hematopoiesis and pten-loss-evoked leukemogenesis

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