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Myc Dependent Synthetic Lethal Targeting Of E If4 F And M Torc1

2567 words - 11 pages

Myc is a transcription factor that is often duplicated or over-expressed in cancer. Myc-driven cancers are often more resistant to treatment and have a worse survival rate than cancers in which Myc expression is normal1-3. Targeting Myc directly has been unsuccessful, therefore it is of interest to find other targets in Myc-driven cancers. The two papers presented here examine Myc-dependent synthetic lethal targets. In Myc-driven cancers, these two groups show that there is a strong reliance upon the eukaryotic initiation factor 4-F (eIF4F) complex, which is important in the initiation of translation. This complex includes a helicase (eIF4A), a scaffolding protein (eIF4G) and a 5’ mRNA Cap-recognizing protein (eIF4E). Together, they recruit the 40S ribosomal subunit and help initiate translation4. It has been shown that Myc promotes the transcription of eIF4A, eIF4E and eIF4G, and that this complex itself promotes the translation of Myc5. Lin et al., 20126 show that targeting this complex directly is lethal to Myc-dependent cancer, but has low toxicity in healthy cells. Pourdehnad et al., 20137 show that regulation of this complex through the targeting of the upstream mammalian target of Rapamycin Complex 1 (mTORC1) is also lethal to Myc-dependent cancers, but not healthy cells. These two groups are targeting a similar pathway and test their theories in similar fashion. Their research presents interesting avenues in the treatment of Myc-driven cancer, yet there are fundamental questions that are unanswered.
Lin et al., Targeting synthetic lethal interactions between Myc and the eIF4F complex impedes tumorigenesis. Cell Reports 2012

The Eμ-Myc mouse is a mouse with Myc translocated to the immunoglobulin heavy chain enhancer, causing a very high expression of Myc in the B cell lineage. This is reminiscent of Burkitt’s Lymphoma. In this paper, these mice had an expanded pre-B cell pool of pre-lymphomatus cells from 4 to 6 weeks of age, which failed to induce cancer in recipient wild type mice (Figures 1A and 1B). It seems that Myc induces hyperproliferation of all cells in the B cell lineage, and that this occurs prior to the eventual development of cancer. These B cells had elevated expression of Myc, as well as downstream genes eIF4E, eIF4A, and eIF4G (Figure 1C).
To study the role of eIF4E in these mice, this group generated transgenic mice which expressed a doxycyclin (dox)-inducible short-hairpin (sh)RNA which would target either eIF4E or the neutral control Luciferase mRNA. Cells that express the shRNAs would also express GFP (Figure 1D). These mice were treated as of 4 weeks of age with dox (Figure 1E). Mice with shRNA targeting eIF4E were conferred longer survival compared to mice not treated with dox, while mice with shRNA-Luciferase had no improved protection. Clearly, eIF4E is important in the development of lymphoma in this model.
Knockdown of eIF4E in Eμ-Myc mice decreased the B cell population (Figure 2A), decreased the...

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