Our study explores mechanisms of translational control in leukemia and we will test new methods of cancer detection and therapy. Specifically, the translation factors eIF4E (4E) and eIF4A (4A) are highly expressed in human T-cell leukemia (T-ALL) specimens. Moreover, both factors act as oncogenic drivers in a murine T-ALL model (Wendel et al. 2004, Wolfe et al. 2014). We want to understand how aberrant translation promotes leukemia development and whether these changes provide opportunities for detection and therapy. Our recent work has shed light on 4A's role in T-ALL (Wolfe et al. 2014): For example, we found that 4A is needed to unwind RNA G-quadruplex (GQ) structures that mark the 5'UTRs of T-ALL oncogenes such as MYC, NOTCH, MYB (Wolfe et al. 2014). Accordingly, selective inhibitors of 4A (e.g. silvestrol) show powerful activity in T- ALL at dose levels that are tolerable in vivo. We will now focus on the translation program driven by the oncogenic 4E factor and further test diagnostic and therapeutic implications of aberrant mRNA translation in cancer. In principle, aberrant translation in cancer may simply increase overall protein production. However, we speculate that oncogenic translation factors like 4E and 4A drive specific translation programs that are encoded in a transcript's regulatory elements. This hypothesis is based on our recent identification of a conserved 4A responsive element in the 5'UTR of ~200 mRNAs in T- ALL (Wolfe et al. 2014).
In Aims 1 and 2 we propose a systematic analysis to define exactly how 4E contributes to oncogenic translation. This is a long-standing interest in the lab and remains an important question in the field.
In Aim 3 we turn to the `translational' aspects and explore how we can use aberrant translation to detect and treat cancer.
Exploring oncogenic translation programs in cancer H.Guido Wendel Project narrative The translation factors eIF4E (4E) and eIF4A (4A) are highly expressed in leukemia and other cancers and they can drive leukemia development in animals. We will explore the translation programs driven by these oncogenic translation factors. We will further explore new ways to utilize aberrant translation in cancer detection and treatment.
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| Boice, Michael; Salloum, Darin; Mourcin, Frederic et al. (2016) Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells. Cell 167:405-418.e13 |
