title: Targeting of active mTOR inhibits primary leukemia T cells and synergizes with cytotoxic drugs and signaling inhibitors.
abstract: OBJECTIVE
  Rationally designed therapies aim at the specific disruption of critical signaling pathways activated by malignant transformation or signals from the tumor microenvironment. Because mammalian target of rapamycin (mTOR) is an important signal integrator and a key translational regulator, we evaluated its potential involvement in T-cell acute lymphoblastic leukemia (T-ALL) and whether mTOR blockade synergizes with chemotherapeutic agents or other signaling antagonists to inhibit primary leukemia T cells.
  
  
  METHODS
  mTOR signaling status was assessed using biochemical, immunostaining, and molecular regulation studies and functional assays performed to assess the impact of mTOR blockade on T-ALL proliferation, survival, and cell cycle.
  
  
  RESULTS
  We observed that mTOR signaling is highly activated in all T-ALL patients tested, with phosphorylation of its downstream substrates eIF4G and S6 ribosomal protein. mTOR activation was detected in vivo and was further increased in vitro by stimulation with interleukin-7, a potentially leukemogenic cytokine normally produced by the bone marrow microenvironment. In T-ALL cells, mTOR blockade was associated with accumulation of the cyclin-dependent kinase inhibitor p27(kip1), which preferentially adopted a nuclear localization. Functional studies using rapamycin or CCI-779 showed a dominant inhibitory effect of mTOR blockade on interleukin-7-induced proliferation, survival, and cell-cycle progression of T-ALL cells. Furthermore, mTOR blockade markedly potentiated the antileukemia effects of dexamethasone and doxorubicin, and showed highly synergistic interactions in combination with specific inhibitors of phosphatidylinositol 3-kinase/Akt and Janus kinase 3 signaling.
  
  
  CONCLUSIONS
  This study shows activation of mTOR signaling in primary T-ALL cells evolving in the leukemic bone marrow, and supports the inclusion of mTOR antagonists in current therapeutic regimens for this cancer.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Mass., USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Batista
authors.forename: João T
authors.initials: JT
authors.lastname: Barata
authors.forename: Elke
authors.initials: E
authors.lastname: Raderschall
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sallan
authors.forename: Nadia
authors.initials: N
authors.lastname: Carlesso
authors.forename: Lee M
authors.initials: LM
authors.lastname: Nadler
authors.forename: Angelo A
authors.initials: AA
authors.lastname: Cardoso
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002867:Chromones / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009025:Morpholines / Q000494:pharmacology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D002867:Chromones; C113920:EIF4G1 protein, human; D004791:Enzyme Inhibitors; D039603:Eukaryotic Initiation Factor-4G; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines; C116180:WHI P131; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C401859:temsirolimus; D003907:Dexamethasone; D004317:Doxorubicin; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D053616:Janus Kinase 3; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus