title: Co-targeting of Akt and Myc inhibits viability of lymphoma cells from Lck-Dlx5 mice.
abstract: Constitutive activation of AKT is a frequent occurrence in the development of human T-cell acute lymphocytic leukemia/lymphomas (T-ALLs), due largely to inactivation of PTEN. Up regulation of MYC is also commonly observed in human T-ALLs. We previously demonstrated that expression of a constitutively active form of Lck-Akt2 alone is sufficient to initiate T-cell lymphoma in mice, and that tumor formation typically requires up regulation of Myc or Dlx5 caused by specific chromosomal rearrangements. Furthermore, Lck-Dlx5 mice develop T-ALLs that consistently acquire overexpression of Myc and activation of Akt, the latter due to loss of Pten expression. Proliferation of T-ALL cells from Lck-Dlx5 mice was found to be highly sensitive to the Akt pathway inhibitors BEZ235 and RAD001, as well as to JQ1, an inhibitor of bromodomain proteins, one of which (BRD4) regulates Myc transcription. Additionally, low concentrations of BEZ235 were found to cooperate with JQ1 to enhance cell cycle arrest. Higher concentrations of BEZ235 (≥0.5 µM) promoted cell death, although the addition of JQ1 did not result in a further increase in apoptosis. In contrast, the specific Myc inhibitor 10058-F4 caused apoptosis, and when combined with BEZ235 (≥0.5 µM), an enhanced effect on apoptosis was consistently observed. In addition, BEZ235 and RAD001 potentiated vincristine-induced apoptosis when the cells were treated with both drugs simultaneously, whereas pretreatment with BEZ235 antagonized the cell-killing effect of vincristine. Collectively, these experimental findings provide rationale for the design of novel combination therapies for T-ALL that includes targeting of AKT and MYC.
authors: a Cancer Biology Program; Fox Chase Cancer Center ; Philadelphia , PA USA.
authors: Yinfei
authors: Y
authors: Tan
authors: Eleonora
authors: E
authors: Sementino
authors: Jianming
authors: J
authors: Pei
authors: Yuwaraj
authors: Y
authors: Kadariya
authors: Timothy K
authors: TK
authors: Ito
authors: Joseph R
authors: JR
authors: Testa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects* / Q000235:genetics; D000068338:Everolimus / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D051379:Mice; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
chemical_list: C561695:(+)-JQ1 compound; C524814:5-(4-ethylbenzylidene)-2-thioxothiazolidin-4-one; D001381:Azepines; C501120:Dlx5 protein, mouse; D018398:Homeodomain Proteins; D007093:Imidazoles; D016271:Proto-Oncogene Proteins c-myc; D011804:Quinolines; D013844:Thiazoles; D014230:Triazoles; D014750:Vincristine; D000068338:Everolimus; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051057:Proto-Oncogene Proteins c-akt; C531198:dactolisib
keywords: Dlx5 homeobox gene; Myc and Akt oncogenes; T cell lymphoma; cell cycle deregulation; mouse tumor model