We have shown that activating protein translation can drive tumorigenesis in mouse models. For example, the eIF4E translation factor can cause tumor development in mice alone or with c-Myc. However, it is unclear exactly how increased translation can promote tumor development. We speculate that the activation of translation directly increases the production of specific anti-apoptotic and oncogenic activities. We will test this hypothesis in our proposal using a mosaic mouse lymphoma model and advanced polyribosome profiling techniques. We previously used a mouse lymphoma model to show the oncogenic effect of translational activation.
In Aim 1 we will use the same mouse model to generate lymphomas in vivo that are driven by translational activation or arise through a translation-independent mechanism. To identify exactly which mRNAs are preferentially translated, we will then use polyribosome fractionation and deep sequencing of ribosome-associated mRNAs. Next, we will test the tumor relevant functions of individual candidate genes in vitro and in our mouse model. Notably, we have identified the anti-apoptotic Mcl1 as a first translationally controlled oncoprotein, and have characterized its function. These experiments will now serve as a template for the study of additional candidates (see preliminary studies and Aim 2).
In Aim 3 we will use our preclinical lymphoma model to test the therapeutic benefit of blocking Mcl1 with small molecule (obatoclax). Mcl1 is highly expressed in some human lymphomas, where it corresponds to markers of translational activation. We speculate that tumors driven by translational activation may show an increased requirement for Mcl1. This preclinical trial is in collaboration with the Lymphoma Service at Memorial Hospital, and will directly feed into their clinical trial on the same compound. Together, this is an innovative study into the biology and clinical relevance of translational regulation in tumorigenesis and therapy. All the necessary tools are in place, e.g. the mosaic mouse model, polyribosome fractionation and 454 sequencing techniques, and our preclinical trial has the potential for near term clinical application. Moreover, our recent publications in Genes &Development indicate a track record of successful studies that have provided new insights in this understudied area of tumor biology.
Cancer is caused by genetic activation cellular signals that drive cell proliferation and oppose cell death. Ultimately, these signals converge on downstream effectors that carry out these functions, these are most often proteins. Our study will characterize changes in protein production (translation) in cancer. A first protein that we have found to be controlled at the level of protein production is Mcl1, which is highly produced in lymphocyte cancers (lymphoma) and makes these tumors resistant to cell death. Notably, a drug that can inhibit this protein exists and we will now test its effect against lymphomas in mice. We speculate that this drug should increase the ability of chemotherapy to induce cell death in tumors. This preclinical trial is the first step to determine whether the drug is suitable for patients, and we are conducting these studies in collaboration with the clinical lymphoma department of Memorial Hospital, so that our results can directly feed into clinical trials. In the long-term, we expect to find other proteins that behave like Mcl1, for most proteins a drug will not yet be available and our study will help define priorities for developing new drugs.
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|Oricchio, Elisa; Ciriello, Giovanni; Jiang, Man et al. (2014) Frequent disruption of the RB pathway in indolent follicular lymphoma suggests a new combination therapy. J Exp Med 211:1379-91|
|Wolfe, Andrew L; Singh, Kamini; Zhong, Yi et al. (2014) RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer. Nature 513:65-70|
|Sanghvi, Viraj R; Mavrakis, Konstantinos J; Van der Meulen, Joni et al. (2014) Characterization of a set of tumor suppressor microRNAs in T cell acute lymphoblastic leukemia. Sci Signal 7:ra111|
|Mets, Evelien; Van Peer, Gert; Van der Meulen, Joni et al. (2014) MicroRNA-128-3p is a novel oncomiR targeting PHF6 in T-cell acute lymphoblastic leukemia. Haematologica 99:1326-33|
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