Selective Translation Research Articles

Abstract 3247: Functional CRISPR-Cas9 screens identify master regulators of resistance to chemical targeting of RNA polymerase I

Abstract Increased ribosome biogenesis is a hallmark of cancer and targeting this process with RNA polymerase I (Pol I) inhibitors is a promising strategy for cancer therapy. BMH-21 is a first-in-class small molecule that inhibits Pol I transcription and induces degradation of the enzyme. This approach is effective across many cancer types. However, a heterogeneous response was observed in cancer cell lines emphasizing the need to increase knowledge of factors that underlie the response to this therapeutic strategy. To identify genes that modulate the response of cancer cells to BMH-21, we performed genome-wide CRISPR-Cas9-based positive selection screens in human colorectal carcinoma cells. These screens identified high-confidence hits accounting for BMH-21 drug resistance that included all key positive regulators of the mTORC1 complex. Given that p53 has been identified as a downstream effector of Pol I transcription stress, we conducted the screens in TP53 isogenic cells. Notably, the mTORC1 pathway hits were identified in all screens indicating that the resistance was p53 independent. These findings are particularly striking given that mTOR is a major driver of ribosome biogenesis and cellular translational programs. The findings were validated using chemical and genetic approaches. Torin-1, a catalytic mTOR inhibitor, was found to cause resistance to BMH-21. mTOR signaling pathway knockout and rescue cell lines were generated and tested for changes in the drug responses by growth, viability, colony formation and GFP competition assays. In each case, compromised mTOR activity led to resistance to BMH-21. However, compromised mTOR activity did not abrogate Pol I transcription inhibition by BMH-21. To assess impact on protein translation, we used polysome profiling. BMH-21 treatment was found to cause a severe ribosome biogenesis defect. Surprisingly, mTOR inactivation partially rescued the translation ability under the drug treatment suggesting that this translation is pivotal for cell survival. To uncover factors critical for the survival, we performed Ribo-seq and RNA-seq in the drug-treated BMH-21 sensitive and resistant cells. The profiling results revealed that mTOR inactivation led to elevated translation efficiency of mRNAs encoding ribosomal proteins. These findings suggest that mTOR inactivation evokes compensatory selective translation of ribosomal proteins under severe ribosome biogenesis defect caused by the Pol I inhibition. The findings indicate that mTOR inactivation regulates selective translation as means to bypass Pol I inhibition, and more generally, that maintenance of translational capacity strongly contributes to treatment resistance. These findings reveal an unexpected complication by mTOR inhibitory strategies as well as have implications on exploring drug combinations in cancer. Citation Format: Wenjun Fan, Hester Liu, Stephanie Pitts, Brittany Ford, Rajeshkumar NV, Marikki Laiho. Functional CRISPR-Cas9 screens identify master regulators of resistance to chemical targeting of RNA polymerase I [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3247.

MEDB-18. Elongation control of mRNA translation supports Group 3 medulloblastoma adaptation to nutrient deprivation

Group 3 affiliation and MYC genetic amplification are associated with poor life expectancy and substantial morbidity in children suffering from medulloblastoma (MB). However, the high metabolic demand induced by MYC-driven transformation sensitizes MYC-overexpressing MB to cell death under conditions of nutrient deprivation (ND). Additionally, MYC-driven transformation is known to promote mitochondrial oxidative phosphorylation (OXPHOS). We previously reported that eukaryotic Elongation Factor Kinase 2 (eEF2K), the master regulator of mRNA translation elongation, promotes survival of MYC-overexpressing tumors under ND. Interestingly, eEF2K is overexpressed in MYC-driven MB and our preliminary proteomics data highlight large-scale alterations in OXPHOS components affecting eEF2K deficient MB cells. We therefore hypothesized that eEF2K activity is required for the selective translation of mRNAs needed for efficient OXPHOS, and for the progression of MYC-driven MB. We pefrormed Multiplexed enhanced Protein Dynamic Mass Spectrometry in eEF2K knockdown MYC-overexpressing D425 MB cells to identify mRNAs selectively translated upon eEF2K activation. Messenger RNAs encoding multiple (9 out of 10 detected) components of the mitochondrial OXPHOS pathway are selectively translated upon eEF2K activation. Inactivation of eEF2K by genetic KO leads to the disassembly of electron transport chain (ETC) complexes I-IV without affecting mRNA levels of their respective components. Consistently, eEF2K KO MB cells display decreased mitochondrial membrane potential and 20% increased proton leak thorough the mitochondrial membrane. In addition, eEF2K inactivation results in increased Group 3 MB cell death under ND and doubles survival of MB bearing mice fed with calorie restricted diets (p< 0.05).Control of mRNA translation elongation by eEF2K is critical for mitochondrial ETC complex assembly and efficient OXPHOS in MYC-overexpressing MB, likely representing an adaptive response by which MYC-driven MB cells cope with acute metabolic stress. Future therapeutic studies will aim to combine eEF2K inhibition with caloric restriction mimetic drugs as eEF2K activity appears critical under metabolic stress conditions.

MODL-18. Enhancing anti-CD47 mAb efficacy with radiotherapy for Group 3 paediatric medulloblastoma in preclinical models

Abstract Medulloblastoma is the most common paediatric brain cancer. Standard treatment approaches, including craniospinal irradiation (CSI), can result in severe lifelong side effects and have not changed for decades resulting in a stagnation of survival outcomes for children with aggressive medulloblastoma. Despite successes in other cancers, no immunotherapies have been approved for use in paediatric medulloblastoma. Unlike other solid tumours, medulloblastomas are myeloid dominant, and immunotherapies must be rationally designed with the tumour microenvironment in mind. Anti-CD47 antibody therapy activates macrophages against cancer cells by blocking anti-phagocytic signalling mediated by CD47-SIRPa ligation and has shown preclinical efficacy in brain cancer models. We have developed preclinical CSI protocols that mimic clinical treatment response using a small animal radiotherapy platform. We show that CSI depletes adaptive immune cells in the brain, increasing the proportional abundance of myeloid cells, suggesting an opportunity to combine radiation with myeloid-targeted immunotherapy. We show that anti-CD47 therapy is ineffective as a single agent against a patient-derived xenograft model of Group 3 medulloblastoma (SJ_MB002), and that while the CSI protocol causes temporary tumour regression, the combination of anti-CD47 with CSI results in marked and persistent tumour regression. To enhance our preclinical evaluation of CSI and anti-CD47, we have developed new mouse models that more accurately reflect the developing microenvironment of children and show that immune populations in paediatric brain are distinct from adult mouse brain. Future work will elucidate the mechanisms by which radiotherapy alters the medulloblastoma microenvironment to enhance the anti-tumour activity of myeloid immune cells in the brain. By evaluating this novel combination of immunotherapy with standard medulloblastoma treatments, in age-appropriate models, our research should facilitate the rational selection and rapid translation of optimised treatment combinations for future medulloblastoma clinical trials.

Transcriptional Role of the Cdk8 Kinase Module with Protein Synthesis Machinery Before and After Nitrogen Starvation

Translation is tightly coupled to growth status. Efficient protein synthesis is necessary for cell growth in nutrient rich environments, while global translation inhibition combined with selective translation of stress‐responsive mRNAs helps limit growth in times of stress. How does the cell alter protein synthesis machinery to survive in stress such as nutrient deprivation? A few mechanisms in nitrogen starvation include selective degradation of specific mRNA‐binding translation factors, inhibition of activators of genes whose products are required for general translation, and the primarily cap‐independent selective translation of mRNAs necessary for the stress response. How and when these occur, however, have remained elusive. Here, we demonstrate in Saccharomyces cerevisiae that the highly conserved Cdk8 kinase module (CKM) of the mediator complex (cyclin C, Cdk8, Med13, and Med12) transcriptionally upregulates genes encoding 60S ribosome proteins and cap‐dependent initiation factors such as eIF4G1 in physiological conditions. Yeast CKM is known to predominantly repress stress response genes (SRG), and our previous findings revealed that SRG suppression is relieved through the degradation of Med13 and cyclin C following both cell survival and death cues. Our recent data suggest that degradation of the CKM following nitrogen starvation may play a transcriptional role in altering the levels of proteins no longer needed for general translation. Additionally, while cyclin C has a secondary role of promoting mitochondrial fragmentation in the cytoplasm following oxidative stress, we have previously found that Med13 goes to the cytoplasm to be degraded via autophagy following nitrogen starvation. Our preliminary data also shows Med13 associating with proteins involved in translation regulation in nitrogen starvation, suggesting it may also have a more direct role in controlling translation. The CKM is thus a multi‐faceted hub that can provide insight to how the cell adapts to stress on both the level of transcription and translation.

Social media text analytics of Malayalam\u2013English code-mixed using deep learning

Zigzag conversational patterns of contents in social media are often perceived as noisy or informal text. Unrestricted usage of vocabulary in social media communications complicates the processing of code-mixed text. This paper accentuates two major aspects of code mixed text: Offensive Language Identification and Sentiment Analysis for Malayalam–English code-mixed data set. The proffered framework addresses 3 key points apropos these tasks—dependencies among features created by embedding methods (Word2Vec and FastText), comparative analysis of deep learning algorithms (uni-/bi-directional models, hybrid models, and transformer approaches), relevance of selective translation and transliteration and hyper-parameter optimization—which ensued in F1-Scores (model’s accuracy) of 0.76 for Forum for Information Retrieval Evaluation (FIRE) 2020 and 0.99 for European Chapter of the Association for Computational Linguistics (EACL) 2021 data sets. A detailed error analysis was also done to give meaningful insights. The submitted strategy turned in the best results among the benchmarked models dealing with Malayalam–English code-mixed messages and it serves as an important step towards societal good.

V. Shalamov’s Kolyma Stories [Kolymskie rasskazy] in translations by J. Glad and D. Rayfield

The article offers a quick historical overview of the English translations of Varlam Shalamov’s Kolyma Stories [Kolymskie rasskazy]. The first translation of a big selection of stories was made by J. Glad: the selected tales were published by W.W. Norton &amp; Company in two volumes (Kolyma Stories in 1980 and Graphite in 1981), to be printed as a single volume in 1994 under the title Kolyma Stories. A new and superior edition appeared in the years 2018 and 2020 — the two-volume Kolyma Stories translated by D. Rayfield; his complete translation is based on the authorial text published in Russia by Shalamov’s literary estate executor I. Sirotinskaya. This ensures that the cycle’s compositional integrity is intact. Agreeing with the opinion expressed by A. Osipova in her review ‘The Forced Conversion of Varlam Shalamov’ in The Los Angeles Review of Books, we recognise Rayfield’s achievements in conveying Shalamov’s terse style and masterful use of detail, including details as symbols or signs — the cornerstone of Shalamov’s writings. Also analysed are the theses in A. Valles’ Introduction to the second volume, which suggest the importance of a philological reading of Shalamov’s works.

Adaptive translational reprogramming of metabolism limits the response to targeted therapy in BRAFV600 melanoma

Despite the success of therapies targeting oncogenes in cancer, clinical outcomes are limited by residual disease that ultimately results in relapse. This residual disease is often characterized by non-genetic adaptive resistance, that in melanoma is characterised by altered metabolism. Here, we examine how targeted therapy reprograms metabolism in BRAF-mutant melanoma cells using a genome-wide RNA interference (RNAi) screen and global gene expression profiling. Using this systematic approach we demonstrate post-transcriptional regulation of metabolism following BRAF inhibition, involving selective mRNA transport and translation. As proof of concept we demonstrate the RNA processing kinase U2AF homology motif kinase 1 (UHMK1) associates with mRNAs encoding metabolism proteins and selectively controls their transport and translation during adaptation to BRAF-targeted therapy. UHMK1 inactivation induces cell death by disrupting therapy induced metabolic reprogramming, and importantly, delays resistance to BRAF and MEK combination therapy in multiple in vivo models. We propose selective mRNA processing and translation by UHMK1 constitutes a mechanism of non-genetic resistance to targeted therapy in melanoma by controlling metabolic plasticity induced by therapy.

MYCT1 alters the glycogen shunt by regulating selective translation of RACK1-mediated enzymes

SummaryMYCT1 has been shown to function as a tumor suppressor in various tumors, but its role in metabolism has never been reported. Here, we showed that global inactivation of Myct1 in mice led to progressive accumulation of glycogen in the liver, which was accompanied by aberrant changes in intermediates of the glycogen metabolic pathway. Mechanistically, MYCT1 appeared to promote translation efficiency of PGM1, UGP2 and GSK3A in hepatic cells in a RACK1-dependent manner. Consequently, upregulation of the three enzymes enhanced the glycogen shunt. Our data reveal a critical role of MYCT1 as a switch for the glycogen shunt in tumor cells.

Selective translation of epigenetic modifiers affects the temporal pattern and differentiation of neural stem cells

The cerebral cortex is formed by diverse neurons generated sequentially from neural stem cells (NSCs). A clock mechanism has been suggested to underlie the temporal progression of NSCs, which is mainly defined by the transcriptome and the epigenetic state. However, what drives such a developmental clock remains elusive. We show that translational control of histone H3 trimethylation in Lys27 (H3K27me3) modifiers is part of this clock. We find that depletion of Fbl, an rRNA methyltransferase, reduces translation of both Ezh2 methyltransferase and Kdm6b demethylase of H3K27me3 and delays the progression of the NSC state. These defects are partially phenocopied by simultaneous inhibition of H3K27me3 methyltransferase and demethylase, indicating the role of Fbl in the genome-wide H3K27me3 pattern. Therefore, we propose that Fbl drives the intrinsic clock through the translational enhancement of the H3K27me3 modifiers that predominantly define the NSC state.

Condensed, Microtubule-coating Thin Organelles for Orthogonal Translation in Mammalian Cells

Membraneless organelles are capable of selectively performing complex tasks in living cells despite dynamically exchanging with their surroundings. This is an exquisite example how self-organization of proteins and RNAs can lead to more complex functionalities in living systems. Importantly, the absence of a membrane boundary can enable easier access to larger macromolecular complexes that can be challenging to be transported across a membrane. We previously formed orthogonally translating designer membraneless organelles by combining phase separation with kinesin motor proteins to highly enrich engineered translational factors in large organelles. We also showed that even submicron thick designer organelles can be formed, by mounting them onto membranes, which, presumable assisted by 2D condensation, leads to thin film-like condensates. In this study we show that orthogonal translation can also be built with fiber-like appearing organelles. Here, the microtubule-end binding protein EB1 was used to form fiber-like OT organelles along the microtubule cytoskeleton that perform highly selective and efficient orthogonal translation. We also show an improved simplified design of OT organelles. Together this extends OT organelle technology and demonstrates that the microtubule cytoskeleton is a powerful platform for advanced synthetic organelle engineering.

EIF3 and Its mRNA-Entry-Channel Arm Contribute to the Recruitment of mRNAs With Long 5'-Untranslated Regions.

Translation initiation in eukaryotes is a multi-step pathway and the most regulated phase of translation. Eukaryotic initiation factor 3 (eIF3) is the largest and most complex of the translation initiation factors, and it contributes to events throughout the initiation pathway. In particular, eIF3 appears to play critical roles in mRNA recruitment. More recently, eIF3 has been implicated in driving the selective translation of specific classes of mRNAs. However, unraveling the mechanism of these diverse contributions—and disentangling the roles of the individual subunits of the eIF3 complex—remains challenging. We employed ribosome profiling of budding yeast cells expressing two distinct mutations targeting the eIF3 complex. These mutations either disrupt the entire complex or subunits positioned near the mRNA-entry channel of the ribosome and which appear to relocate during or in response to mRNA binding and start-codon recognition. Disruption of either the entire eIF3 complex or specific targeting of these subunits affects mRNAs with long 5′-untranslated regions and whose translation is more dependent on eIF4A, eIF4B, and Ded1 but less dependent on eIF4G, eIF4E, and PABP. Disruption of the entire eIF3 complex further affects mRNAs involved in mitochondrial processes and with structured 5′-untranslated regions. Comparison of the suite of mRNAs most sensitive to both mutations with those uniquely sensitive to disruption of the entire complex sheds new light on the specific roles of individual subunits of the eIF3 complex.

ПЕР. СТ.: РИФФЕР Ф. СОЗНАНИЕ: ТОЧКА ЗРЕНИЯ ФИЛОСОФИИ ПРОЦЕССА И ГЕНЕТИЧЕСКОГО СТРУКТУРАЛИЗМА - КРИТИЧЕСКОЕ СРАВНЕНИЕ И НЕКОТОРЫЕ ПОСЛЕДСТВИЯ

A selective translation of the article by the Austrian philosopher, theologian, psychologist and teacher from the Department of Pedagogical Sciences of the University of Salzburg F. Riffer seems appropriate, since it highlights the modern philosophical debates about the phenomenon of consciousness based on D. Chalmers' distinction between its easy and difficult problems. A.N. Whitehead's philosophy of the process provides a promising basis for solving a difficult problem in connection with the rootedness of the concept of consciousness in metaphysical theory. Whitehead's reflection is compared with the results of empirical studies of the phenomena of consciousness of J. Piaget. If they partially coincide, the position of the former seems to be more reasonable. This corresponds to W.E. Seeger's suggestion to pay more attention to processalism or the concept of a philosophical process. Whitehead's point of view on learning, consciousness and artificial intelligence is considered.

Huck’s Adventures in India: Cultural Conversation in Select Hindi Adaptations

Scholarly studies in India have acknowledged the role of Mark Twain’s writings in critiquing social justice in a transnational framework. However, in the popular sphere Twain is seen primarily as a writer of tales of boyhood adventure, and his relevance to current social issues has not been fully realized. In the context of Twain’s stature in India, this essay analyzes the degree to which select juvenile translations of Adventures of Huckleberry Finn in Hindi (one of India’s official languages) have been able to harness the potential of this text to dismantle deep-seated prejudices among younger readers, socializing them into a culture of tolerance. Critiquing the range of translational efforts in two versions of juvenile readers (in both a descriptive and prospective way), the essay assesses the degree to which these translations have succeeded or failed in this endeavor. It also explores the structural and linguistic options for future translations in Hindi which could overcome the shortcomings of the existing texts, thereby tapping into the novel’s value as an instructional text for readers of an impressionable age.

Tetrahydropalmatine attenuates liver fibrosis by suppressing endoplasmic reticulum stress in hepatic stellate cells.

Tetrahydropalmatine attenuates liver fibrosis by suppressing endoplasmic reticulum stress in hepatic stellate cells.

Ribosomal Protein 6 Phosphorylation Regulates Translational Responses to Dietary Restriction

Many older adults prefer to live within their community because they have built strong relationships with their neighbors and neighborhood. Although housing-related factors promote aging in place, findings on the relationships of late-life challenges to aging in place (e.g., cost of living, autonomy) and relocation are mixed. Less is known about the types of challenges to aging in place and about the relationship between the types of challenges and relocation. Using data from the AARP 2015 Age-Friendly Community Surveys (N=3,190 adults aged 65 and older), this study examined the intersection of challenges to aging in place (e.g., home size, cost, safety, independence, family, transportation) and relocation (i.e., move to a different home outside of their community). Using latent class analysis (LCA), we identified five subgroups of late-life challenges to aging in place: multifaceted challenges, cost of living, independence, social connection, no concern. Findings from LCA with a distal outcome showed that older adults with multifaceted challenges (b=0.77, p<.001), were more likely to move out of their community, compared to those with lower levels of challenges, even after adjusting for age, sex, education, income, and chronic diseases. Also, those with challenges regarding the cost of living (b=0.84, p<.001), independence (b=0.64, p<.001), and family connection (b=0.45, p<.001) were more likely to expect to move out of their community. The findings highlight that older adults have different types of challenges to aging in place. Practitioners and policymakers should provide more individualized supportive services, considering the types of challenges to promote aging in place.

Visualization-based improvement of neural machine translation

We introduce a novel visual-interactive approach for analyzing, understanding, and correcting neural machine translation. Our system supports users in automatically translating documents using neural machine translation and identifying and correcting possible erroneous translations. User corrections can then be used to fine-tune the neural machine translation model and automatically improve the whole document. While translation results of neural machine translation can be impressive, there are still many challenges such as over- and under-translation, domain-specific terminology, and handling long sentences, making it necessary for users to verify translation results. Our system aims at supporting users in this task. Our visual analytics approach combines several visualization techniques in an interactive system. A parallel coordinates plot with multiple metrics related to translation quality can be used to find, filter, and select translations that might contain errors. An interactive beam search visualization and graph- or matrix-based visualizations for attention weights can be used for post-editing and understanding machine-generated translations. The machine translation model is updated from user corrections to improve the translation quality of the whole document. We designed our approach for an LSTM-based translation model and extended it to also include the Transformer architecture. We show for representative examples possible mistranslations and how to use our system to deal with them. A user study revealed that many participants favor such a system over manual text-based translation, especially for translating large documents. Furthermore, we performed quantitative computer-based experiments that show that our system can be used to improve translation quality and reduce post-editing efforts for domain-specific documents.

Towards Offensive Language Identification for Tamil Code-Mixed YouTube Comments and Posts

Offensive Language detection in social media platforms has been an active field of research over the past years. In non-native English spoken countries, social media users mostly use a code-mixed form of text in their posts/comments. This poses several challenges in the offensive content identification tasks, and considering the low resources available for Tamil, the task becomes much harder. The current study presents extensive experiments using multiple deep learning, and transfer learning models to detect offensive content on YouTube. We propose a novel and flexible approach of selective translation and transliteration techniques to reap better results from fine-tuning and ensembling multilingual transformer networks like BERT, Distil- BERT, and XLM-RoBERTa. The experimental results showed that ULMFiT is the best model for this task. The best performing models were ULMFiT and mBERTBiLSTM for this Tamil code-mix dataset instead of more popular transfer learning models such as Distil- BERT and XLM-RoBERTa and hybrid deep learning models. The proposed model ULMFiT and mBERTBiLSTM yielded good results and are promising for effective offensive speech identification in low-resourced languages.

Introduction

Abstract This roundtable revolves around the translation of selections from Amel's book Is the Heart for the East and Reason for the West? On Edward Said's Marx in “Orientalism,” published in Arabic in 1986. The importance of bringing this Arabic text to an English and global readership is twofold: it sheds light on the work of an influential and widely read Arabic critical social theorist and philosopher; and the translation of this critical theoretical work from “the margin” opens up central epistemological and conceptual problems in Marxist theory and its relation to postcolonialism in the present. The work of translation here does not simply involve introducing a marginal novelty into mainstream critical theory; rather it is a process of exhuming the elements that are untranslatable in the text—that is, the conceptual problems that have universal implications from within the particular site of their articulation.

Study on Fuzzy ELECTRE Method with Various Methodologies

The purpose of this thesis is to develop a MCDM system based on a deletion and selective translation reality (ELECTRE) Assessment information is expressed and manipulated by the Tempster-Schaefer Theory (DST). DST is the primary means for uncertainty modeling. In this paper, the weight of the criteria and the effectiveness of each alternative are expressed in terms of linguistic terms and belief levels, which are then converted into basic probability assignment (BPA) representations. In order to integrate the evaluations of different experts in the most rational and efficient manner, a discount system in DST is provided Based on the proposed concept of source reliability. In addition, as a family of MCDM models, the ELECTRE system is known for its superior relationships in ordering a set of alternatives. As an extension, artificial weight, including subjective and objective weights, is used to determine concepts of synchronization and variance. The proposed DS-ELECTRE approach directly reflects the advantage of DST and deals with uncertainty, but the ELECTRE method can also play a role in analyzing the relationships between alternatives. An illustrative number example is conducted to demonstrate the effectiveness of the DS-ELECTRE method. The final result matrix can be obtained based on the fusion results, which will then be used in ELECTRE mode. At this point, the transcendental relationships between all pair alternatives are structured in ELECTRE mode using concepts of synchronization and contrast, which are Represented by some corresponding matrix. A result chart will be drawn based on the resulting global matrix, and the ranking results will be analyzed to determine the appropriate provider. In short, a new ELECTRE-based system has been developed to address MCDM issues in DST contexts, which can be considered by decision makers. non-formal evaluation and apply incomplete or insufficient knowledge of data. Therefore, in this study, a comprehensive Weight including subjective weight and objective weight is defined in the process of ELECTRE method to make the synchronization and contrast metrics more reasonable. Subjective weight is obtained only on the basis of decision makers ’preferences or judgments, and objective weight is determined using the entropy weight method.

CSIG-23. ELONGATION CONTROL OF mRNA TRANSLATION DRIVES GROUP 3 MEDULLOBLASTOMA ADAPTATION TO NUTRIENT DEPRIVATION

Abstract Group 3 affiliation and MYC genetic amplification are associated with poor life expectancy and substantial morbidity in children suffering from medulloblastoma (MB). However, the high metabolic demand induced by MYC-driven transformation sensitizes MYC-overexpressing MB to cell death under conditions of nutrient deprivation (ND). Additionally, MYC-driven transformation is known to promote mitochondrial oxidative phosphorylation (OXPHOS). We previously reported that eukaryotic Elongation Factor Kinase 2 (eEF2K), the master regulator of mRNA translation elongation, promotes survival of MYC-overexpressing tumors under ND. Interestingly, eEF2K is overexpressed in MYC-driven MB and our preliminary proteomics data highlight large-scale alterations in OXPHOS components affecting eEF2K deficient MB cells. We therefore hypothesized that eEF2K activity is required for the selective translation of mRNAs needed for efficient OXPHOS, and for the progression of MYC-driven MB. We pefrormed Multiplexed enhanced Protein Dynamic Mass Spectrometry in eEF2K knockdown MYC-overexpressing D425 MB cells to identify mRNAs selectively translated upon eEF2K activation. Messenger RNAs encoding multiple (9 out of 10 detected) components of the mitochondrial OXPHOS pathway are selectively translated upon eEF2K activation. Inactivation of eEF2K by genetic KO leads to the disassembly of electron transport chain (ETC) complexes I-IV without affecting mRNA levels of their respective components. Consistently, eEF2K KO MB cells display decreased mitochondrial membrane potential and 20% increased proton leak thorough the mitochondrial membrane. In addition, eEF2K inactivation results in increased Group 3 MB cell death under ND and doubles survival of MB bearing mice fed with calorie restricted diets (p&amp;lt; 0.05). Control of mRNA translation elongation by eEF2K is critical for mitochondrial ETC complex assembly and efficient OXPHOS in MYC-overexpressing MB, likely representing an adaptive response by which MYC-driven MB cells cope with acute metabolic stress. Future therapeutic studies will aim to combine eEF2K inhibition with caloric restriction mimetic drugs as eEF2K activity appears critical under metabolic stress conditions.