mTORC1 is essential for leukemia propagation but not stem cell self-renewal
01 Jun 2012-Journal of Clinical Investigation (American Society for Clinical Investigation)-Vol. 122, Iss: 6, pp 2114-2129
TL;DR: Transplantation of Raptor-deficient undifferentiated AML cells in a limiting dilution revealed that mTORC1 is essential for leukemia initiation, and it was demonstrated that the reactivation of m TORC1 in those cells restored their leukemia-initiating capacity.
Abstract: Although dysregulation of mTOR complex 1 (mTORC1) promotes leukemogenesis, how mTORC1 affects established leukemia is unclear. We investigated the role of mTORC1 in mouse hematopoiesis using a mouse model of conditional deletion of Raptor, an essential component of mTORC1. Raptor deficiency impaired granulocyte and B cell development but did not alter survival or proliferation of hematopoietic progenitor cells. In a mouse model of acute myeloid leukemia (AML), Raptor deficiency significantly suppressed leukemia progression by causing apoptosis of differentiated, but not undifferentiated, leukemia cells. mTORC1 did not control cell cycle or cell growth in undifferentiated AML cells in vivo. Transplantation of Raptor-deficient undifferentiated AML cells in a limiting dilution revealed that mTORC1 is essential for leukemia initiation. Strikingly, a subset of AML cells with undifferentiated phenotypes survived long-term in the absence of mTORC1 activity. We further demonstrated that the reactivation of mTORC1 in those cells restored their leukemia-initiating capacity. Thus, AML cells lacking mTORC1 activity can self-renew as AML stem cells. Our findings provide mechanistic insight into how residual tumor cells circumvent anticancer therapies and drive tumor recurrence.
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TL;DR: In this paper, double-stranded (ds)DNAs were transferred to the donor cells to dampen their hematopoietic capabilities during stem cell transplantation (HSCT) in mouse myeloid leukemia models.
Abstract: Accumulating evidence indicates the presence of cytoplasmic DNAs in various types of malignant cells, and its involvement in anti-cancer drug- or radiotherapy-mediated DNA damage response and replication stress. However, the pathophysiological roles of cytoplasmic DNAs in leukemias remain largely unknown. We observed that during hematopoietic stem cell transplantation (HSCT) in mouse myeloid leukemia models, double-stranded (ds)DNAs were constitutively secreted in the form of extracellular vesicles (EVs) from myeloid leukemia cells and were transferred to the donor cells to dampen their hematopoietic capabilities. Subsequent analysis of cytoplasmic DNA dynamics in leukemia cells revealed that autophagy regulated cytoplasmic dsDNA accumulation and subsequent redistribution into EVs. Moreover, accumulated cytoplasmic dsDNAs activated STING pathway, thereby reducing leukemia cell viability through reactive oxygen species (ROS) generation. Pharmaceutical inhibition of autophagosome formation induced cytoplasmic DNA accumulation, eventually triggering cytoplasmic DNA sensing pathways to exert cytotoxicity, preferentially in leukemia cells. Thus, manipulation of cytoplasmic dsDNA dynamics can be a novel and potent therapeutic strategy for myeloid leukemias.
4 citations
TL;DR: As the knowledge of the genetics of myeloid leukemia improves with additional integrated profiling efforts, it will lead to more accurate animal models and facilitate translational efforts in the leukemia field.
4 citations
Dissertation•
20 Nov 2014
TL;DR: In this article, the authors show that l’activation of mTORC1 (mammalian target of rapamycin complex) is a condition necessaire a linduction de la mort cellulaire.
Abstract: Les leucemies aigues myeloides (LAM) representent un groupe d’hemopathies malignes agressives, de pronostic sombre en depit des traitements intensifs actuellement proposes Malgre une grande heterogeneite clinique et moleculaire, les cellules de LAM sont caracterisees par l’activation de voies de signalisation essentielles a leur proliferation et leur survie, comme par exemple celle du complexe mTORC1 (mammalian target of rapamycin complex 1) Cependant, l’utilisation clinique d’inhibiteurs tels que la rapamycine ou des inhibiteurs catalytiques s’est averee decevante, ce qui suggere qu’il n’y a pas d’addiction oncogenique a mTORC1 dans les LAM Au cours de ce travail, nous avons demontre que l’activation de mTORC1 est au contraire une condition necessaire a l’induction de la mort cellulaire en reponse a l’activation d’AMPK (AMP-activated protein kinase), etablissant une relation de letalite synthetique entre ces deux voies Pour cela, nous avons utilise un nouveau compose activateur specifique d’AMPK, le GSK621 En invalidant la sous-unite catalytique AMPKα1 par ARN interference ou par le systeme CRISPR/Cas9, nous avons demontre que les effets antileucemiques de ce compose sont bien dependants de l’activation d’AMPK Nous avons observe que ce compose favorise l’autophagie, et que ce processus est implique dans la mort des cellules leucemiques puisque l’inhibition des proteines ATG5 ou ATG7 a un effet protecteur sur les cellules leucemiques Les effets antileucemiques du compose GSK621 ont ete confirmes sur des cellules primaires, ainsi que sur un panel de vingt lignees de LAM, et dans un modele murin de xenogreffe De facon interessante, l’activation d’AMPK pourrait egalement compromettre la survie des cellules souches leucemiques, comme en atteste l’attenuation du potentiel clonogenique en methylcellulose de cellules murines transformees par MLL-ENL ou FLT3-ITD Nous avons observe que le compose GSK 621 n’avait pas de toxicite envers les progeniteurs hematopoietiques normaux, ouvrant ainsi une fenetre therapeutique interessante Comme l’activation d’AMPK conduit dans de nombreux modeles cellulaires a l’inhibition de mTORC1, et comme l’activation de mTORC1 est observee dans les cellules de LAM mais pas dans les progeniteurs hematopoietiques normaux, nous avons propose l’hypothese que le niveau d’activation de mTORC1 determinait les effets de l’activateur d’AMPK Pour cela, nous avons inhibe mTORC1 dans les cellules leucemiques d’une part, et active mTORC1 dans les progeniteurs normaux d’autre part De facon inattendue, mTORC1 echappe au controle d’AMPK dans les LAM, et nous avons observe que l’activation de mTORC1 est une condition necessaire et suffisante pour que le compose GSK621 entraine la mort des cellules Le substrat moleculaire de cette letalite synthetique est le facteur de transcription proapoptotique ATF4, dont la transcription est favorisee par mTORC1, et la traduction par AMPK via la phosphorylation d’eIF2A Ces travaux proposent donc que malgre l’absence d’addiction oncogenique, l’activation de mTORC1 dans les LAM represente une opportunite therapeutique originale via une relation de letalite synthetique avec l’activation d’AMPK Ils constituent un rationnel au developpement clinique d’activateurs d’AMPK dans les LAM, voire dans d’autres cancers ayant une activation constitutive de mTORC1
4 citations
Cites background from "mTORC1 is essential for leukemia pr..."
...L’invalidation conditionnelle de RAPTOR dans un modèle murin de LAM a permis de mieux cerner le rôle de mTORC1 dans cette pathologie (Hoshii et al., 2012)....
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TL;DR: Lysosome’s involvement in the critical biological processes has rekindled clinical interest towards this organelle for treating various diseases, including cancer, and the functions and importance of targeting lysosomes in AML are summarized.
Abstract: Simple Summary Lysosomes are a critical component of the inner membrane system and are involved in various cellular biological processes, including macromolecular degradation, antigen presentation, intracellular pathogen destruction, plasma membrane repair, exosome release, cell adhesion/migration, and apoptosis. Lysosomes are a critical regulator of cellular metabolism, cancer, metastasis, and resistance to anticancer therapy. Additionally, lysosomal activities play a crucial role in acute myeloid leukemia (AML) development and progression, as well as maintaining the hematopoietic stem cells (HSCs) pool. It has been shown that AML cells undergo metabolic alterations due to chemotherapy or targeted treatment. Thus, depending on the molecular subtypes of AML or the treatments involved, lysosomes could have a therapeutic potential. Abstract Lysosomes are cellular organelles that regulate essential biological processes such as cellular homeostasis, development, and aging. They are primarily connected to the degradation/recycling of cellular macromolecules and participate in cellular trafficking, nutritional signaling, energy metabolism, and immune regulation. Therefore, lysosomes connect cellular metabolism and signaling pathways. Lysosome’s involvement in the critical biological processes has rekindled clinical interest towards this organelle for treating various diseases, including cancer. Recent research advancements have demonstrated that lysosomes also regulate the maintenance and hemostasis of hematopoietic stem cells (HSCs), which play a critical role in the progression of acute myeloid leukemia (AML) and other types of cancer. Lysosomes regulate both HSCs’ metabolic networks and identity transition. AML is a lethal type of blood cancer with a poor prognosis that is particularly associated with aging. Although the genetic landscape of AML has been extensively described, only a few targeted therapies have been produced, warranting the need for further research. This review summarizes the functions and importance of targeting lysosomes in AML, while highlighting the significance of lysosomes in HSCs maintenance.
4 citations
TL;DR: It is found that FASN mRNA levels were significantly higher in AML patients than in healthy granulocytes or CD34+ hematopoietic progenitors in two AML cohorts.
Abstract: Acute myeloid leukemia (AML) is a blood cancer characterized by a block in differentiation and increased survival of the resulting AML blast cells. While standard chemotherapy for AML cures only 30% of patients, differentiation-inducing therapy using all-trans retinoic acid (ATRA) in combination with arsenic trioxide achieves 90% cure rates in acute promyelocytic leukemia (APL). A better understanding of the molecular mechanisms underlying ATRA therapy in APL may provide new perspectives in the treatment of additional AML subtypes. Fatty acid synthase (FASN) is the only human lipogenic enzyme available for de novo fatty acid synthesis. While FASN levels are very low in healthy adult tissues, it is often highly expressed in cancer cells, thus representing a potential therapeutic target. We found that FASN mRNA levels were significantly higher in AML patients than in healthy granulocytes or CD34+ hematopoietic progenitors in two AML cohorts (n=68, n=203) (p
4 citations
References
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TL;DR: Stem cell biology has come of age: Unequivocal proof that stem cells exist in the haematopoietic system has given way to the prospective isolation of several tissue-specific stem and progenitor cells, the initial delineation of their properties and expressed genetic programmes, and the beginnings of their utility in regenerative medicine.
Abstract: Stem cell biology has come of age. Unequivocal proof that stem cells exist in the haematopoietic system has given way to the prospective isolation of several tissue-specific stem and progenitor cells, the initial delineation of their properties and expressed genetic programmes, and the beginnings of their utility in regenerative medicine. Perhaps the most important and useful property of stem cells is that of self-renewal. Through this property, striking parallels can be found between stem cells and cancer cells: tumours may often originate from the transformation of normal stem cells, similar signalling pathways may regulate self-renewal in stem cells and cancer cells, and cancer cells may include 'cancer stem cells' - rare cells with indefinite potential for self-renewal that drive tumorigenesis.
8,999 citations
TL;DR: It is reported that mTOR forms a stoichiometric complex with raptor, an evolutionarily conserved protein with at least two roles in the mTOR pathway that through its association with mTOR regulates cell size in response to nutrient levels.
2,902 citations
"mTORC1 is essential for leukemia pr..." refers result in this paper
...Although mTORC1 reportedly controls cell size (cell growth) (34), we did not observe a decrease in the size of our Raptor-deficient AML cells (Figure 6B), and we found that the amount of protein per cell was comparable in control and Raptor-deficient AML stem cells (Figure 6, C and D)....
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TL;DR: It is shown that rapamycin inhibits the assembly of mTORC2 and that, in many cell types, prolongedRapamycin treatment reduces the levels of m TORC2 below those needed to maintain Akt/PKB signaling.
2,621 citations
"mTORC1 is essential for leukemia pr..." refers background in this paper
...We found that Raptor deficiency did not affect the expression level of Rictor, an essential component of mTORC2, but it is possible that long-term inactivation of mTORC1 in Raptordeficient AML cells affects the assembly and activity of mTORC2, leading to inhibition of AKT, in the same manner as prolonged rapamycin treatment (49)....
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...On the other hand, prolonged rapamycin treatment is reported to suppress AKT via the disassembly of the mTORC2 complex in certain cell types (49)....
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TL;DR: The data suggest that feedback down-regulation of receptor tyrosine kinase signaling is a frequent event in tumor cells with constitutive mTOR activation, and reversal of this feedback loop by rapamycin may attenuate its therapeutic effects, whereas combination therapy that ablates mTOR function and prevents Akt activation may have improved antitumor activity.
Abstract: Stimulation of the insulin and insulin-like growth factor I (IGF-I) receptor activates the phosphoinositide-3-kinase/Akt/mTOR pathway causing pleiotropic cellular effects including an mTOR-dependent loss in insulin receptor substrate-1 expression leading to feedback down-regulation of signaling through the pathway. In model systems, tumors exhibiting mutational activation of phosphoinositide-3-kinase/Akt kinase, a common event in cancers, are hypersensitive to mTOR inhibitors, including rapamycin. Despite the activity in model systems, in patients, mTOR inhibitors exhibit more modest antitumor activity. We now show that mTOR inhibition induces insulin receptor substrate-1 expression and abrogates feedback inhibition of the pathway, resulting in Akt activation both in cancer cell lines and in patient tumors treated with the rapamycin derivative, RAD001. IGF-I receptor inhibition prevents rapamycin-induced Akt activation and sensitizes tumor cells to inhibition of mTOR. In contrast, IGF-I reverses the antiproliferative effects of rapamycin in serum-free medium. The data suggest that feedback down-regulation of receptor tyrosine kinase signaling is a frequent event in tumor cells with constitutive mTOR activation. Reversal of this feedback loop by rapamycin may attenuate its therapeutic effects, whereas combination therapy that ablates mTOR function and prevents Akt activation may have improved antitumor activity.
2,423 citations
"mTORC1 is essential for leukemia pr..." refers background in this paper
...org Volume 122 Number 6 June 2012 (32, 33), neither Raptor deficiency nor rapamycin resulted in hyperphosphorylation of AKT (S473) (Figure 6A and Supplemental Fig-...
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TL;DR: Recent findings on the regulators and effectors of mTOR are highlighted and specific cases that serve as paradigms for the different modes of m TOR regulation and its control of translation are discussed.
Abstract: The process of translation requires substantial cellular resources. Cells have therefore evolved complex mechanisms to control overall protein synthesis as well as the translation of specific mRNAs that are crucial for cell growth and proliferation. At the heart of this process is the mammalian target of rapamycin (mTOR) signalling pathway, which senses and responds to nutrient availability, energy sufficiency, stress, hormones and mitogens to modulate protein synthesis. Here, we highlight recent findings on the regulators and effectors of mTOR and discuss specific cases that serve as paradigms for the different modes of mTOR regulation and its control of translation.
2,328 citations
"mTORC1 is essential for leukemia pr..." refers background in this paper
...These target molecules control cell growth (size) and proliferation by modifying protein translation (1)....
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