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        Exploring the ribosomal stress pathway as a targetable vulnerability in TP53 aberrant Acute Lymphoblastic leukemia

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        Writing Assingment - SR- Final Version.pdf (938.4Kb)
        Publication date
        2023
        Author
        Reijers, Sacha
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        Summary
        Acute Lymphoblastic Leukemia (ALL) is one of the most frequently diagnosed cancers in children. Although the survival rates have been increasing, relapses are still occurring, which are generally hard to cure. Especially relapses showing aberrations in TP53 predict a dismal outcome due to their high resistance against most chemotherapeutic drugs, but also novel immune therapies that have entered the clinic. Therefore, there is an urgent clinical need for better therapies for TP53 deleted ALL. In the last decade the ribosome biogenesis (RiBi) pathway has emerged as an effective target in cancer therapy. RiBi is known to play a role in oncogenic signalling pathways and is therefore highly regulated to maintain cellular homeostasis. Monitoring of RiBi is managed by ribosomal stress signaling pathways that can sense both through p53 or be p53-independent. The role of the ribosomal stress pathway in the development of ALL is underlined by the presence of somatic mutations in several ribosomal proteins that all have been linked to contribute to T-ALL progression. In a study to find new vulnerabilities of TP53 aberrant ALL, they identified eEF2K as a new vulnerable target. eEF2K is a protein which negatively regulates translation elongation and can be activated upon many different stresses, including ribosomal stress. eEF2K is also under investigation as a possible novel molecular target for cancer treatment. In this review I have explored the ribosomal stress pathway as a potential targetable vulnerability in p53 aberrant ALL in order to provide a mechanistic explanation for the observed synthetic lethality between loss of TP53 function and loss of eEF2K in ALL under conditions of cellular stress. For this I reviewed different p53-(in)dependent ribosomal stress signalling pathways, looked at how aberrations in RiBi and these pathways can be linked to cancer development, and how these pathways can be used as a target for the development of new and improved anticancer therapies. Finally, I examined the role of eEF2K, its connection to ribosomal stress and its contribution to cancer progression.
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        https://studenttheses.uu.nl/handle/20.500.12932/43661
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