An In Vivo CRISPR Screening Platform for Prioritizing Therapeutic Targets in AML

CRISPR-Cas9-based genetic screens have successfully identified cell type-dependent liabilities in cancer, including acute myeloid leukemia (AML), a devastating hematologic malignancy with poor overall survival. Because most of these screens have been performed in vitro using established cell lines, evaluating the physiologic relevance of these targets is critical. We have established a CRISPR screening approach using orthotopic xenograft models to validate and prioritize AML-enriched dependencies in vivo, including in CRISPR-competent AML patient-derived xenograft (PDX) models tractable for genome editing. Our integrated pipeline has revealed several targets with translational value, including SLC5A3 as a metabolic vulnerability for AML addicted to exogenous myo-inositol and MARCH5 as a critical guardian to prevent apoptosis in AML. MARCH5 repression enhanced the efficacy of BCL2 inhibitors such as venetoclax, further highlighting the clinical potential of targeting MARCH5 in AML. Our study provides a valuable strategy for discovery and prioritization of new candidate AML therapeutic targets. SIGNIFICANCE: There is an unmet need to improve the clinical outcome of AML. We developed an integrated in vivo screening approach to prioritize and validate AML dependencies with high translational potential. We identified SLC5A3 as a metabolic vulnerability and MARCH5 as a critical apoptosis regulator in AML, both of which represent novel therapeutic opportunities.This article is highlighted in the In This Issue feature, p. 275

Un traité astronomique et météorologique syriaque attribué à Denys l'aréopagite

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Une inscription syriaque de Biredjik

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Saint Jérôme et la vie de Paul de Thèbes

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La compilation historique de Pseudo-Zacharie le Rhéteur

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Nouvelle note sur l'inscription trilingue de Zébed

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Remarques sur les traductions syriaques des formules grecques: o tès eusebous leszos et o tès osias mnèmès

La pagination indiquée dans la zone "Pages" est celle du tiré à part, numérisé par les Bibliothèques de l'ULB. La pagination telle qu'elle apparaît dans la revue est pp. 155-160.info:eu-repo/semantics/publishe

Note sur l'inscription trilingue de Zébed

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Web-based tool for recombinase-based state machine design and visualization

Thesis: M. Eng., Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science, 2017.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student-submitted PDF version of thesis.Includes bibliographical references (pages 59-61).Biological state machines have the potential to enable a wide range of applications but until recently have been challenging to implement experimentally. To overcome this challenge, we described a scalable strategy for assembling biological state machines using recombinases. This platform enables the implementation of biological state machines with arbitrary behaviors, but the manual design of such state machines is increasingly challenging with increasing complexities. Here, we introduce RSMLab, an intuitive web-based application for creating circuits that implement state-dependent logic in living cells using our scalable state-machine framework. Through a graphical user interface, RSMLab users choose a desired state diagram, define arbitrary genes, and specify whether those genes are on or off in each state. RSMLab then returns a visualization of possible gene circuits that correspond to the user specifications. We use the RSMLab algorithm and demonstrate the circuit design process using examples of two-input, five-state and three-input, sixteen-state gene regulation programs. With the help of RSMLab, researchers can program state-dependent logic to study and program the way that cells respond to combinational and temporally distributed chemical events, without needing to be expert gene circuit engineers. We envision that biology-focused design software such as RSMLab will enable the faster, more reliable, and more accessible creation of DNA-encoded circuits for engineering complex cellular behaviors.by Guillaume Georges Kugener.M. Eng