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Analysis of gene expression array in TSC2-deficient AML cells reveals IRF7 as a pivotal factor in the Rheb/mTOR

V Makovski1, J Jacob-Hirsch2, C Gefen-Dor2

  • 1Department of Neurobiology, The George S Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel.

Cell Death & Disease
|December 6, 2014
PubMed

Insights

S-trans,trans-farnesylthiosalicylic acid (FTS) inhibits Rheb and attenuates proliferation in tuberous sclerosis complex (TSC)-deficient cells. FTS and rapamycin treatments alter interferon regulatory factor 7 (IRF7) targets, suggesting FTS as a potential therapeutic for TSC-related conditions.

Area of Science:

  • Oncology
  • Genetics
  • Immunology

Background:

  • Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in TSC genes, leading to neoplasms like lymphangioleiomyomatosis (LAM) and angiomyolipomas (AMLs).
  • TSC-deficient cells exhibit chronic activation of the Rheb/mammalian target of rapamycin complex 1 (mTORC1) pathway, which can be targeted by inhibitors.
  • AML cells with TSC mutations serve as a model for studying TSC and LAM due to shared genetic alterations.

Purpose of the Study:

  • To investigate the effects of inhibiting the Rheb/mTORC1 pathway on TSC2-deficient AML cells.
  • To explore the potential of S-trans,trans-farnesylthiosalicylic acid (FTS) as a therapeutic agent for TSC and related pathologies.
  • To identify downstream molecular targets affected by Rheb/mTORC1 inhibition in TSC-deficient cells.

Main Methods:

  • Utilized human TSC2-deficient AML cells derived from a LAM patient.
  • Administered FTS to inhibit Rheb and attenuated cell proliferation.
  • Performed comparative gene array analysis following treatments with FTS, rapamycin, or TSC2 re-expression.

Main Results:

  • FTS treatment inhibited Rheb and reduced proliferation in TSC2-deficient AML cells.
  • Gene array analysis revealed commonly altered genes, many identified as downstream targets of interferon (IFN) regulatory factor 7 (IRF7).
  • Nuclear localization of IRF7 was impaired by FTS, rapamycin, or TSC2 re-expression, with effects selective for TSC2-deficient cells.

Conclusions:

  • FTS demonstrates potential as a therapeutic agent for TSC and associated conditions by targeting the Rheb/mTORC1 pathway.
  • Interferon regulatory factor 7 (IRF7) emerges as a novel therapeutic target in TSC-related pathologies.
  • The study highlights the intricate link between mTORC1 signaling, IRF7, and the immune response in TSC pathogenesis.

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