The long-range goal of this project is to define the mechanisms by which the mammalian target of rapamycin (mTOR) and mRNA translation contribute to the pathogenesis of chronic myelogenous leukemia (CML). mTOR is a central controller of cell growth, proliferation, and apoptosis in response to growth factors and the availability of nutrients. The mTOR effectors, S6K and 4E-BP1/eIF4E, mediate these effects by regulating ribosome biogenesis and cap-dependent translation. The central hypothesis guiding this application is that mTOR signaling contributes to cr-Abl-driven leukemogenesis. To test this hypothesis, this investigator's laboratory has found that several mTOR effectors are modulated by Bcr-Abl. They have also identified a subset of genes that are regulated by mTOR and Bcr-Abl in CML cells. Combined inhibition of the Bcr-Abl and mTOR kinases was also found to act synergistically to kill CML cells, and overcome imatinib-resistance. This proposal has two specific aims.
Aim 1 will test the hypothesis that mTOR signaling contributes to Bcr-Abl-mediated leukemogenesis via altered translation. The contribution of eIF4E, S6K, and specific genes that are translationally regulated by Bcr-Abl will be investigated by using genetic and biochemical approaches.
Aim 2 will determine the mechanisms by which rapamycin enhances imatinib-killing of CML cells. These studies will be accomplished by interfering with 4E-BP1 and S6K function, by using a combination of dominant negative mutants, as well as siRNA. These studies are likely to lead to novel approaches to target CML, as well as other cancers characterized by dysregulation of the PI3K/Akt/mTOR axis. The clinical relevance of these studies is further underlined by the planned opening of a Phase I clinical trial of the mTOR inhibitor, CCI-779, in combination with imatinib mesylate in patients with high-risk CML in the fall of 2004.
| Tsai, Becky Pinjou; Jimenez, Judith; Lim, Sharon et al. (2014) A novel Bcr-Abl-mTOR-eIF4A axis regulates IRES-mediated translation of LEF-1. Open Biol 4:140180 |
| Zhang, Min; Fu, Wuxia; Prabhu, Sharmila et al. (2008) Inhibition of polysome assembly enhances imatinib activity against chronic myelogenous leukemia and overcomes imatinib resistance. Mol Cell Biol 28:6496-509 |
| Prabhu, S; Saadat, D; Zhang, M et al. (2007) A novel mechanism for Bcr-Abl action: Bcr-Abl-mediated induction of the eIF4F translation initiation complex and mRNA translation. Oncogene 26:1188-200 |
| Moore, James C; Dennehey, Carolyn F; Anavim, Arash et al. (2006) Multiple joint effusions associated with high-dose imatinib therapy in a patient with chronic myelogenous leukaemia. Eur J Haematol 76:444-6 |
