Journal
CANCER DISCOVERY
Volume 3, Issue 1, Pages 82-95Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-12-0404
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Funding
- Novartis
- Pfizer
- National Health and Medical Research Council of Australia [166908, 251688, 509087, 400116, 454569, 251608, 566702, 400120, 566876]
- Cancer Council Victoria
- Leukaemia Foundation of Australia
- Victorian Cancer Agency
- Susan G. Komen for the Cure Foundation
- Australian Rotary Health Foundation
- National Cancer Institute
- Cancer Council of Victoria
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MYC deregulation is common in human cancer. IG-MYC translocations that are modeled in E mu-Myc mice occur in almost all cases of Burkitt lymphoma as well as in other B-cell lymphoproliferative disorders. Deregulated expression of MYC results in increased mTOR complex 1 (mTORC1) signaling. As tumors with mTORC1 activation are sensitive to mTORC1 inhibition, we used everolimus, a potent and specific mTORC1 inhibitor, to test the requirement for mTORC1 in the initiation and maintenance of E mu-Myc lymphoma. Everolimus selectively cleared premalignant B cells from the bone marrow and spleen, restored a normal pattern of B-cell differentiation, and strongly protected against lymphoma development. Established E mu-Myc lymphoma also regressed after everolimus therapy. Therapeutic response correlated with a cellular senescence phenotype and induction of p53 activity. Therefore, mTORC1-dependent evasion of senescence is critical for cellular transformation and tumor maintenance by MYC in B lymphocytes.
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