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Vital roles of mTOR complex 2 in Notch-driven thymocyte differentiation and leukemia

Keunwook Lee1, Ki Taek Nam, Sung Hoon Cho

  • 1Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.

The Journal of Experimental Medicine
|April 5, 2012
PubMed

Insights

Mammalian target of rapamycin complex 2 (mTORC2) promotes T-cell acute lymphoblastic leukemia (T-ALL) driven by Notch signaling. mTORC2 is crucial for Notch to regulate Akt and NF-κB, impacting T-ALL progression and cell invasion.

Area of Science:

  • Cell Biology
  • Cancer Biology
  • Immunology

Background:

  • Notch signaling is vital for cell fate decisions and tumorigenesis.
  • The phosphatidylinositol 3-kinase/target of rapamycin (TOR) pathway is activated by Notch.
  • The role of mammalian target of rapamycin complex 2 (mTORC2) in Notch-driven outcomes is unclear.

Purpose of the Study:

  • To investigate the contribution of mTORC2 to Notch-driven thymic T-cell acute lymphoblastic leukemia (T-ALL).

Main Methods:

  • Conditional deletion of Rictor, an mTORC2 component, in thymocytes.
  • Assessment of Notch-driven proliferation, differentiation, and NF-κB activity.
  • Analysis of CCR7 expression and tissue invasion in T-ALL models.

Main Results:

  • Rictor deletion impaired Notch-driven T-cell proliferation and differentiation.
  • NF-κB activity and Akt signaling were dependent on mTORC2 integrity.
  • mTORC2 depletion reduced CCR7 expression, tissue invasion, and mortality in T-ALL.

Conclusions:

  • mTORC2 plays a critical role in promoting thymic T-cell development and T-ALL.
  • mTORC2 is essential for Notch signaling to regulate Akt and NF-κB pathways in T-ALL.

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