mTORC1 is essential for leukemia propagation but not stem cell self-renewal
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Cites background from "mTORC1 is essential for leukemia pr..."
...Phosphorylation of p62 and induction of Nqo1 both decreased upon As(III) exposure in MEFs lacking Raptor (Hoshii et al., 2012), a component of the mTORC1 complex (Figures S2B and S2C)....
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262 citations
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Cites background from "mTORC1 is essential for leukemia pr..."
...Conversely, the deletion of the MTORC1 component RAPTOR, therefore theoretically causing an increase in autophagy, results in a decrease of this myeloid population.(91) However, it remains to be shown definitively that loss or gain of autophagy contributes to this phenotype, as MTOR inhibition signals for many other important cellular functions such as inhibition of protein translation, mitochondrial biogenesis, cell growth, motility and proliferation....
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238 citations
Cites background from "mTORC1 is essential for leukemia pr..."
...Recently, it was shown in a raptor deficiency mouse model thatmTORC1 inactivation induces apoptosis in differentiated leukemic cells and maintains immature leukemic cells with leukemia initiation potential in a dormant state, underlying the critical role of mTORC1 in leukemia.(4) In vitro, in primary AML cells, mTORC1 inhibition with rapamycin has cytostatic effects but does not induce apoptosis,(2-5) mainly because it does not inhibit 4E-BP1 phosphorylation on ser65....
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References
155 citations
"mTORC1 is essential for leukemia pr..." refers background in this paper
...org Volume 122 Number 6 June 2012 rapamycin and ATP-competitive mTOR inhibitors (26, 27)....
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...of mTORC1, including Raptor, 4E-BP1/2, AKTS1 (also known as PRAS40), and LARP1 (26, 27)....
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...Among these molecules, there were several known downstream targets of mTORC1, including Raptor, 4E-BP1/2, AKTS1 (also known as PRAS40), and LARP1 (26, 27)....
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...Feedback activation of the PI3K/AKT pathway is triggered by inhibition of Grb10 and/or activation of IRS after acute mTORC1 inactivation (26, 27)....
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144 citations
"mTORC1 is essential for leukemia pr..." refers methods in this paper
...To create a representative AML model, we first inserted the MLL-AF9 fusion gene (17, 18, 21) into K+S+L– cells isolated from Raptorfl/fl, Raptor+/+CreER, or Raptorfl/flCreER mice by using retrovirus-mediated transfer....
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118 citations
114 citations
"mTORC1 is essential for leukemia pr..." refers background in this paper
...Because eIF4E overexpression reportedly increases cell size and resistance to rapamycin treatment (41, 42), the increased presence of eIF4E protein on cap structures may compensate for the inhibition of eIF4E activity by 4E-BP1, leading to the retained cell growth and self-renewal in the absence of mTORC1....
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...Decreased phosphorylation of AKTS1, as well as of 4E-BPs, is reportedly associated with apoptosis in tumor cells (41)....
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112 citations
"mTORC1 is essential for leukemia pr..." refers background in this paper
...mutation revealed that phosphorylation of S6 after GM-CSF stimulation is highly dependent on MEK/ERK signaling, but not on PI3K/AKT signaling (29)....
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