Dual mTORC2/mTORC1 targeting results in potent suppressive effects on Acute Myeloid Leukemia (AML) progenitors

Jessica K. Altman, Antonella Sassano, Surinder Kaur, Heather Glaser, Barbara Kroczynska, Amanda J. Redig, Suzanne Russo, Sharon Barr, Leonidas C. Platanias

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

Abstract

Purpose: To determine whether mTORC2 and rapamycin-insensitive (RI)-mTORC1 complexes are present in acute myeloid leukemia (AML) cells and to examine the effects of dual mTORC2/mTORC1 inhibition on primitive AML leukemic progenitors. Experimental Design: Combinations of different experimental approaches were used, including immunoblotting to detect phosphorylated/activated forms of elements of the mTOR pathway in leukemic cell lines and primary AML blasts; cell-proliferation assays; direct assessment of mRNA translation in polysomal fractions of leukemic cells; and clonogenic assays in methylcellulose to evaluate leukemic progenitor-colony formation. Results: mTORC2 complexes are active in AML cells and play critical roles in leukemogenesis. RImTORC1 complexes are also formed and regulate the activity of the translational repressor 4E-BP1 in AML cells. OSI-027 blocks mTORC1 and mTORC2 activities and suppresses mRNA translation of cyclin D1 and other genes that mediate proliferative responses in AML cells. Moreover, OSI-027 acts as a potent suppressor of primitive leukemic precursors from AML patients and is much more effective than rapamycin in eliciting antileukemic effects in vitro. Conclusions: Dual targeting of mTORC2 and mTORC1 results in potent suppressive effects on primitive leukemic progenitors from AML patients. Inhibition of the mTOR catalytic site with OSI-027 results in suppression of both mTORC2 and RI-mTORC1 complexes and elicits much more potent antileukemic responses than selectivemTORC1 targeting with rapamycin.

Original languageEnglish (US)
Pages (from-to)4378-4388
Number of pages11
JournalClinical Cancer Research
Volume17
Issue number13
DOIs
StatePublished - Jul 1 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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