S6K1 regulates hematopoietic stem cell self-renewal and leukemia maintenance

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

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2621-2625
Number of pages5
JournalJournal of Clinical Investigation
Volume126
Issue number7
DOIs
StatePublished - Jul 1 2016

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Ribosomal Protein S6 Kinases
Hematopoietic Stem Cells
Leukemia
Maintenance
Oncogene Fusion
Carrier Proteins
Stem Cells
Eukaryotic Initiation Factor-4E
Cell Self Renewal
Neoplasms
Phosphorylation
mechanistic target of rapamycin complex 1
TOR complex 2

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ghosh, J., Kobayashi, M., Ramdas, B., Chatterjee, A., Ma, P., Mali, R. S., ... Kapur, R. (2016). S6K1 regulates hematopoietic stem cell self-renewal and leukemia maintenance. Journal of Clinical Investigation, 126(7), 2621-2625. https://doi.org/10.1172/JCI84565

S6K1 regulates hematopoietic stem cell self-renewal and leukemia maintenance. / Ghosh, Joydeep; Kobayashi, Michihiro; Ramdas, Baskar; Chatterjee, Anindya; Ma, Peilin; Mali, Raghuveer Singh; Carlesso, Nadia; Liu, Yan; Plas, David R.; Chan, Rebecca; Kapur, Reuben.

In: Journal of Clinical Investigation, Vol. 126, No. 7, 01.07.2016, p. 2621-2625.

Research output: Contribution to journalArticle

Ghosh J, Kobayashi M, Ramdas B, Chatterjee A, Ma P, Mali RS et al. S6K1 regulates hematopoietic stem cell self-renewal and leukemia maintenance. Journal of Clinical Investigation. 2016 Jul 1;126(7):2621-2625. https://doi.org/10.1172/JCI84565
Ghosh, Joydeep ; Kobayashi, Michihiro ; Ramdas, Baskar ; Chatterjee, Anindya ; Ma, Peilin ; Mali, Raghuveer Singh ; Carlesso, Nadia ; Liu, Yan ; Plas, David R. ; Chan, Rebecca ; Kapur, Reuben. / S6K1 regulates hematopoietic stem cell self-renewal and leukemia maintenance. In: Journal of Clinical Investigation. 2016 ; Vol. 126, No. 7. pp. 2621-2625.
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