S6K1 regulates hematopoietic stem cell self-renewal and leukemia maintenance
Joydeep Ghosh, … , Rebecca J. Chan, Reuben Kapur
Joydeep Ghosh, … , Rebecca J. Chan, Reuben Kapur
Published June 13, 2016
Citation Information: J Clin Invest. 2016;126(7):2621-2625. https://doi.org/10.1172/JCI84565.
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Brief Report Hematology

S6K1 regulates hematopoietic stem cell self-renewal and leukemia maintenance

Abstract

Hyperactivation of the mTOR pathway impairs hematopoietic stem cell (HSC) functions and promotes leukemogenesis. mTORC1 and mTORC2 differentially control normal and leukemic stem cell functions. mTORC1 regulates p70 ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E–binding (eIF4E-binding) protein 1 (4E-BP1), and mTORC2 modulates AKT activation. Given the extensive crosstalk that occurs between mTORC1 and mTORC2 signaling pathways, we assessed the role of the mTORC1 substrate S6K1 in the regulation of both normal HSC functions and in leukemogenesis driven by the mixed lineage leukemia (MLL) fusion oncogene MLL-AF9. We demonstrated that S6K1 deficiency impairs self-renewal of murine HSCs by reducing p21 expression. Loss of S6K1 also improved survival in mice transplanted with MLL-AF9–positive leukemic stem cells by modulating AKT and 4E-BP1 phosphorylation. Taken together, these results suggest that S6K1 acts through multiple targets of the mTOR pathway to promote self-renewal and leukemia progression. Given the recent interest in S6K1 as a potential therapeutic target in cancer, our results further support targeting this molecule as a potential strategy for treatment of myeloid malignancies.

Authors

Joydeep Ghosh, Michihiro Kobayashi, Baskar Ramdas, Anindya Chatterjee, Peilin Ma, Raghuveer Singh Mali, Nadia Carlesso, Yan Liu, David R. Plas, Rebecca J. Chan, Reuben Kapur

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Figure 2

S6K1 regulates quiescence of HSCs following regeneration from myeloablative stress.

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S6K1 regulates quiescence of HSCs following regeneration from myeloablat...
(A) BM LSK frequency in WT and S6k1–/– mice following a single dose of 5-FU; mean ± SEM. *P < 0.03, t test. n = 8–18/group. (B) Quantitative representation of BrdU+ LSK cells in the BM of WT and S6k1–/– mice on the ninth day after 5-FU treatment; mean ± SEM. *P < 0.05, t test. n = 3/group. Data are representative of 2 independent experiments. (C) Expression levels of Ccng1 in BM LSK cells of WT and S6k1–/– mice on ninth day after 5-FU treatment. Data are from a representative experiment performed twice independently. Experiments performed in quadruplicates; mean ± SD. *P < 0.01. (D) Kaplan-Meier survival curve of WT and S6k1–/– mice treated with weekly doses of 5-FU. *P < 0.001. n = 11–15/group. (E) Kaplan-Meier survival curve of WT mice transplanted with WT and S6k1–/– HSC/Ps and treated with weekly doses of 5-FU. *P < 0.007. n = 10/group. (F) WT and S6k1–/– mice were treated with a single dose of 5-FU. After 6 days, MNCs from treated mice were transplanted into lethally irradiated recipients at a dilution of 1:8. Quantitative representation of donor-derived cells in PB of recipients is shown; mean ± SEM. n = 3/group. *P < 0.05, 1-way ANOVA.